Processes for the preparation of pyrrolidine intermediates

ABSTRACT

The present invention relates to processes for the enantio-selective preparation of spyrrolidine derivatives useful in the manufacture of pesticidally active compounds, as well as to intermediates in the processes. The processes include those comprising 
     (a-i) reacting a compound of formula Ia 
                         
wherein
 
P is alkyl, aryl or heteroaryl, each optionally substituted, wherein the heteroaryl is connected at P via a ring carbon atom;
 
R 1  is chlorodifluoromethyl or trifluoromethyl;
 
R 2  is aryl or heteroaryl, each optionally substituted;
 
with a source of cyanide in the presence a chiral catalyst to give a compound of formula IIa
 
                         
wherein P, R 1  and R 2  are as defined for the compound of formula Ia; and
 
(a-ii) oxidizing the compound of formula IIa with a peroxy acid, or peroxide in the presence of an acid to give a compound of formula VI
 
                         
wherein R 1  and R 2  are as defined for the compound of formula Ia.

This application is a 371 filing of International Application No.PCT/EP2012/069171, filed Sep. 28, 2012, which claims priority benefit toInternational Application No. PCT/EP2011/067224 filed Oct. 3, 2011 andU.S. Provisional Patent Application No. 61/576,135 filed Dec. 15, 2011,the contents of all of which are incorporated herein by reference.

The present invention relates to the synthesis of intermediates usefulfor the preparation of substituted pyrrolidine derivatives, includingthose having pesticidal activity. The invention relates moreparticularly to the stereoselective syntheses of these intermediates

Certain pyrrolidine derivatives with insecticidal properties aredisclosed in, for example WO2008/128711, WO2010043315, WO2011/080211.Such pyrrolidine derivatives include at least one chiral centre at oneof the ring members of the pyrrolidine moiety. The present inventionprovides a process for selectively synthesizing enantiomers of suchcompounds as well as intermediates that can be used in the synthesis ofsuch compounds.

A route to enantio-enriched intermediates is desirable in view of thedifferential biological activity of the enantiomers. Use ofenantio-enriched intermediates can therefore reduce the amount of activeingredient needed to control key pests, thereby reducing costs andimpact on the environment.

Accordingly, in a first aspect the invention provides a process for theenantio-selective preparation of a pyrrolidine derivative comprising

(a-i) reacting a compound of formula Ia

whereinP is alkyl, aryl or heteroaryl, each optionally substituted, wherein theheteroaryl is connected at P via a ring carbon atom;R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;with a source of cyanide in the presence a chiral catalyst to give acompound of formula IIa

wherein P, R¹ and R² are as defined for the compound of formula Ia; and(a-ii) oxidising the compound of formula IIa with a peroxy acid, orperoxide in the presence of an acid, preferably a strong acid, to give acompound of formula VI

wherein R¹ and R² are as defined for the compound of formula Ia.The ability to prepare compounds of formula VI from compounds of formulaIIa via the Baeyer-Villiger oxidation reaction was unexpected andprovides an efficient route to enantio-enriched pyrrolidine derivatives,and can also be applied to reactions with racemic mixtures.In one embodiment step (a-ii) comprises oxidising the compound offormula IIa with a peroxide in the presence of a strong acid to give acompound of formula VI.In addition, the reaction optionally comprises(a-iii-1) reducing the compound of formula VI with a suitable reducingagent to give a compound of formula IX

wherein R¹ and R² are as defined for the compound of formula Ia.and optionally(a-iv-1) reacting the compound of formula IX with a compound of formula(XIII)X^(B)-A′  (XIII)wherein X^(B) is a leaving group such as halogen, and A′ is optionallysubstituted aryl or optionally substituted heteroaryl to give a compoundof formula XVI

wherein R¹ and R² are as defined for the compound of formula Ia and A′is as defined for the compound of formula XIII;or the reaction optionally comprises(a-iii-2) reacting the compound of formula VI with a compound of formulaXIII to give a compound of formula XII

wherein R¹ and R² are as defined for the compound of formula Ia and A′is as defined for the compound of formula XIII;and optionally(a-iv-2) reducing the compound of formula XII with a suitable reducingagent to give a compound of formula XVI.In a further aspect the invention provides a process for theenantio-selective preparation of a pyrrolidine derivative comprising(a-1) reacting a compound of formula Ia

whereinP is alkyl, aryl or heteroaryl, each optionally substituted, wherein theheteroaryl is connected at P via a ring carbon atom;R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;with a source of cyanide in the presence a chiral catalyst to give acompound of formula IIa

wherein P, R¹ and R² are as defined for the compound of formula Ia; and(a-2) oxidizing the compound of formula II a with a peroxide to give acompound of formula XVIII

wherein P, R¹ and R² are as defined for the compound of formula Ia; and(a-3) reducing the compound of formula XVIII with a suitable reducingagent to give a compound of formula III

wherein R¹ and R² are as defined for the compound of formula Ia; andand wherein the reaction optionally comprises(a-4-1) reducing the compound of formula III with a suitable reducingagentto give a compound of formula IX

wherein R¹ and R² are as defined for the compound of formula Ia;and optionally(a-5-1) reacting the compound of formula IX with a compound of formula(XIII)X^(B)-A′  (XIII)wherein X^(B) is a leaving group such as halogen, and A′ is optionallysubstituted aryl or optionally substituted heteroaryl to give a compoundof formula XVI

wherein R¹ and R² are as defined for the compound of formula Ia and A′is as defined for the compound of formula XIII;or the reaction optionally comprises(a-4-2) reacting the compound of formula III with a compound of formula(XIII) to give a compound of formula XVII

wherein R¹ and R² are as defined for the compound of formula Ia and A′is as defined for the compound of formula XIII;and optionally(a-5-2) reducing the compound of formula XVII with a suitable reducingagent to give a compound of formula XVI.In a further aspect the invention provides a process for theenantio-selective preparation of a pyrrolidine derivative comprising(b-i) reacting a compound of formula Ib

whereinP is optionally substituted heteroaryl, and wherein the heteroarylcontains at least one ring nitrogen or oxygen atom, wherein theheteroaryl is connected at P via a ring carbon atom;R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;with a source of cyanide in the presence a chiral catalyst to give acompound of formula IIb

wherein P, R¹ and R² are as defined for the compound of formula Ib; and(b-ii-1) oxidatively cleaving the compound of formula IIb to give acompound of formula XIX

wherein R¹ and R² are as defined for the compound of formula Ib; and(b-ii-2) hydrolysing and dehydrating the compound of formula XIX to givea compound of formula VI

wherein R¹ and R² are as defined for the compound of formula Ib;wherein dehydration is performed in the presence of acid; or(b-ii) reductively cyclising the compound of formula IIb with a suitablereducing agent to give a compound of formula III

wherein R¹ and R² are as defined for the compound of formula I.In a further aspect the invention provides a process for theenantio-selective preparation of a pyrrolidine derivative comprising(c-ii) reductively cyclising the compound of formula IIb with a suitablereducing agent to give a compound of formula III

wherein R¹ and R² are as defined for the compound of formula I;(c-i) reacting a compound of formula I

whereinP is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl orheteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom,R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;with a source of cyanide in the presence a chiral catalyst to give acompound of formula II

wherein P, R¹ and R² are as defined for the compound of formula I; and(c-ii) reductively cyclising the compound of formula II with a suitablereducing agent to give a compound of formula III

wherein R¹ and R² are as defined for the compound of formula I; or(c-iii-1) partially hydrolysing the compound of formula II to give acompound of formula V

wherein P, R¹ and R² are as defined for the compound of formula I; and(c-iii-2) cyclising the compound of formula V, e.g. by heating, to givea compound of formula VI

wherein R¹ and R² are as defined for the compound of formula I; or(c-iv-1) hydrolysing the compound of formula II to give a compound offormula VII

wherein R¹ and R² are as defined for the compound of formula I; and(c-iv-2) cyclising the compound of formula VII, e.g. by heating, to givea compound of formula VI

wherein R¹ and R² are as defined for the compound of formula I; or(c-v-1) reducing the compound of formula II with a suitable reducingagent to give a compound of formula VIII

wherein R¹ and R² are as defined for the compound of formula I; and(c-v-2) treating the compound of formula VIII with a suitable activatingagent to give a compound of formula IX

wherein R¹ and R² are as defined for the compound of formula I; or(c-vi-1) hydrolysing the compound of formula II to give a compound offormula X

wherein R¹ and R² are as defined for the compound of formula I; and(c-vi-2) reacting the compound of formula X with a compound of formulaXIH₂N-A′  (XI)wherein A′ is optionally substituted aryl or optionally substitutedheteroaryl to give a compound of formula XII

wherein R¹ and R² are as defined for the compound of formula I and A′ isas defined for the compound of formula XI; or(c-vii-1) reducing the compound of formula I with a suitable reducingagent to give a compound of formula IV

wherein P, R¹ and R² are as defined for the compound of formula I; and(c-vii-2) reacting the compound of formula IV with a compound of formulaXIIIX^(B)-A′  (XIII)wherein A′ is as defined for the compound of formula XII and X^(B) is aleaving group, e.g. halogen such as bromo, to give a compound of formulaXIV

wherein P, R¹ and R² are as defined for the compound of formula I and A′is as defined for the compound of formula XII; and(c-vii-3) reducing the compound of formula XIV with a suitable reducingagent to give a compound of formula XV

wherein R¹ and R² are as defined for the compound of formula I and A′ isas defined for the compound of formula XII; and(c-vii-4) treating the compound of formula XV with a suitable activatingagent to give a compound of formula XVI

wherein R¹ and R² are as defined for the compound of formula I and A′ isas defined for the compound of formula XII; or(c-viii-1) preparing a compound of formula XIV as described in a-vii-2;(c-viii-2) cyclising the compound of formula XIV, e.g. by heating, togive a compound of formula XVII

wherein R¹ and R² are as defined for the compound of formula I and A′ isas defined for the compound of formula XII.In a further aspect the invention provides a process for theenantio-selective preparation of a pyrrolidine derivative comprising(d-i) reacting a compound of formula II

whereinP is hydroxy, alkoxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl,each optionally substituted, and wherein the heteroaryl contains atleast one ring nitrogen atom, and the heteroaryl is connected at P via aring nitrogen atom,R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;with a nitromethane in the presence a chiral catalyst to give a compoundof formula XX.

wherein P, R¹ and R² are as defined for the compound of formula I; and(d-ii-1) reducing the compound of formula XX with a suitable reducingagent to give a compound of formula IV

wherein P, R¹ and R² are as defined for the compound of formula I; and(d-ii-2) cyclising the compound of formula IV, e.g. by heating, to givea compound of formula III

wherein R¹ and R² are as defined for the compound of formula I; or(d-iii-1) reducing the compound of formula XX with a suitable reducingagent to give a compound of formula VIII

wherein R¹ and R² are as defined for the compound of formula I; and(d-iii-2) treating the compound of formula VIII with an activating agentto give a compound of formula IX

wherein R¹ and R² are as defined for the compound of formula I.In a further aspect the invention provides a process for theenantio-selective preparation of a pyrrolidine derivative comprising(e-i) reacting a compound of formula XXI

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;with a compound of formula XXII

P is hydroxy, alkoxy, alkylsulfinyl, arylsulfinyl, aryl or heteroaryl,each optionally substituted, and wherein the heteroaryl contains atleast one ring nitrogen atom, and the heteroaryl is connected at P via aring nitrogen atom; and(e-ii-1) reducing the compound of formula XX with a suitable reducingagent to give a compound of formula IV

wherein P, R¹ and R² are as defined for the compound of formula I; and(e-ii-2) cyclising the compound of formula IV, e.g. by heating, to givea compound of formula III

wherein R¹ and R² are as defined for the compound of formula I; or(e-iii-1) reducing the compound of formula XX with a suitable reducingagent to give a compound of formula VIII

wherein R¹ and R² are as defined for the compound of formula I; and(e-iii-2) treating the compound of formula VIII with an activatingagent, such as SOCl₂ to give a compound of formula IX

wherein R¹ and R² are as defined for the compound of formula I.

In a further aspect the invention provides a process for theenantio-selective preparation of a pyrrolidine derivative comprising

(f-i) reacting a compound of formula XXI

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;with a compound of formula XXIII

wherein R¹⁰⁰ is alkyl, aryl or heteroaryl, each optionally substituted;in the presence of a chiral catalyst to give a compound of formula XXIV

wherein R¹, R² are as defined for the compound of formula XXI and R¹⁰⁰is as defined for the compound of formula XXIII; and(f-ii) reductively cyclising the compound of formula XXIV with asuitable reducing agent to give a compound of formula XXV

wherein R¹, R² are as defined for the compound of formula XXI and R¹⁰⁰is as defined for the compound of formula XXIII; and(f-iii) treating the compound of formula XXV with base followed bytreatment with acid to give a compound of formula III

wherein R¹ and R² are as defined for the compound of formula XXI.The processes of the invention may also comprise one or more of thefollowing:

-   -   reducing a compound of formula III to a compound of formula IX        with a suitable reducing agent;    -   reducing a compound of formula IV to a compound of formula III        with a suitable reducing agent;    -   reducing a compound of formula IV to a compound of formula IX        with a suitable reducing agent;    -   reducing a compound of formula XII to a compound of formula XVII        with a suitable reducing agent;    -   reducing a compound of formula XII to a compound of formula XVI        with a suitable reducing agent;    -   reducing a compound of formula XVII to a compound of formula XVI        with a suitable reducing agent.

Suitable reducing agents for the above processes will be apparent to theperson skilled in the art, and are examples are described in more detailbelow.

In a further aspect the invention provides a compound of formula IIc

whereinP is alkyl, hydroxy, alkoxy, aryloxy, alkylsulfinyl, or arylsulfinyl,each optionally substituted;R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula III

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula IV

whereinP is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl orheteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom,R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula V

whereinP is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl orheteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom,R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula VI

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula VII

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula VIII

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula IX

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula X

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula XII

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;A′ is optionally substituted aryl or optionally substituted heteroaryl.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula XIV

whereinP is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl orheteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom,R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;A′ is optionally substituted aryl or optionally substituted heteroaryl.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula XV

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;A′ is optionally substituted aryl or optionally substituted heteroaryl.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula XVI

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;A′ is optionally substituted aryl or optionally substituted heteroaryl.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula XVII

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;A′ is optionally substituted aryl or optionally substituted heteroaryl.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula XVIII

whereinP is alkyl, aryl or heteroaryl, each optionally substituted, wherein theheteroaryl is connected at P via a ring carbon atom;R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of IIc and a compound of formula IIIA

whereinP is alkyl, hydroxy, alkoxy, aryloxy, alkylsulfinyl, or arylsulfinyl,each optionally substituted;R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;wherein the mixture is enriched for the compound of formula IIc.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula III and a compound of formula IIIA

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;wherein the mixture is enriched for the compound of formula III.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula IV and a compound of formula WA

P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl orheteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom,R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula V and a compound of formula VA

whereinP is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl orheteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom,R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted wherein themixture is enriched for the compound of formula V.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula VI and a compound of formula VIA

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;wherein the mixture is enriched for the compound of formula VI.In a further aspect the invention provides a mixture comprising acompound of formula VII and a compound of formula VIIA

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;wherein the mixture is enriched for the compound of formula VII.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula VIII and a compound of formula VIIIA

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;wherein the mixture is enriched for the compound of formula VIII.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula IX and a compound of formula IXA

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;wherein the mixture is enriched for the compound of formula IX.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula X and a compound of formula XA

R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;wherein the mixture is enriched for the compound of formula X.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula XII and a compound of formula XIIA

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;A′ is optionally substituted aryl or optionally substituted heteroaryl;wherein the mixture is enriched for the compound of formula XII.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula XIV and a compound of formula XIVA

whereinP is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl orheteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom,R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;A′ is optionally substituted aryl or optionally substituted heteroaryl;wherein the mixture is enriched for the compound of formula XIV.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula XV and a compound of formula XVA

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;A′ is optionally substituted aryl or optionally substituted heteroaryl;wherein the mixture is enriched for the compound of formula XV.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula XVI and a compound of formula XVIA

whereinR¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;A′ is optionally substituted aryl or optionally substituted heteroaryl;wherein the mixture is enriched for the compound of formula XVI.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula XVII and a compound of formula XVIIA

R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;A′ is optionally substituted aryl or optionally substituted heteroaryl;wherein the mixture is enriched for the compound of formula XVII.Preferred substituent definitions are given below.In a further aspect the invention provides a mixture comprising acompound of formula XVIII and a compound of formula XVIIIA

whereinP is alkyl, aryl or heteroaryl, each optionally substituted, wherein theheteroaryl is connected at P via a ring carbon atom;R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;wherein the mixture is enriched for the compound of formula XVIII.Preferred substituent definitions are given below.In a further aspect the invention provides a compound of formula XXIX.In a further aspect the invention provides a compound of formula XXX.In a further aspect the invention provides a compound of formula XXXI.In a further aspect the invention provides a compound of formula XXXII.In a further aspect the invention provides a compound of formula XXXIII.

In the above compounds R¹ and R² are as defined for the compound offormula IIa.In a further aspect the invention provides a mixture comprising acompound of formula XXIX and a compound of formula XXIXA, wherein themixture is enriched for the compound of formula XXIX.In a further aspect the invention provides a compound of formula XXX anda compound of formula XXXA wherein the mixture is enriched for thecompound of formula XXX.In a further aspect the invention provides a compound of formula XXXIand a compound of formula XXXIA wherein the mixture is enriched for thecompound of formula XXXI.In a further aspect the invention provides a compound of formula XXXIIand a compound of formula XXXIIA wherein the mixture is enriched for thecompound of formula XXXII.In a further aspect the invention provides a compound of formula XXXIIIand a compound of formula XXXIIA wherein the mixture is enriched for thecompound of formula XXXII.The compound of formula XXIXA, XXXA, XXXIA, XXXIIA and XXXIIIA have theopposite stereochemistry to XXIX, XXX, XXXI, XXXII and XXXIII at thecarbon bonded to R¹ and R².In a further aspect the invention provides a process for preparingpyrrolidine derivatives comprising(a-i) reacting a compound of formula Ia

whereinP is alkyl, aryl or heteroaryl, each optionally substituted, wherein theheteroaryl is connected at P via a ring carbon atom;R¹ is chlorodifluoromethyl or trifluoromethyl;R² is aryl or heteroaryl, each optionally substituted;with a source of cyanide to give a compound of formula IIa

wherein P, R¹ and R² are as defined for the compound of formula Ia; and(a-ii) oxidising the compound of formula IIa with a peroxide in thepresence of strong acid to give a compound of formula VI-1

wherein R¹ and R² are as defined for the compound of formula Ia.The cyanide addition can be done in presence of a base and/or acatalyst. Examples of bases include triethyl amine, sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide.Examples of chiral catalysts include crown ethers and phase transfercatalysts such as tetrabutylammonium bromide.In addition, the reaction optionally comprises(a-iii-1) reducing the compound of formula VI-1 with a suitable reducingagent to give a compound of formula IX-1

wherein R¹ and R² are as defined for the compound of formula Ia.and optionally(a-iv-1) reacting the compound of formula IX with a compound of formula(XIII)X^(B)-A′  (XIII)wherein X^(B) is a leaving group such as halogen, and A′ is optionallysubstituted aryl or optionally substituted heteroaryl to give a compoundof formula XVI-1

wherein R¹ and R² are as defined for the compound of formula Ia and A′is as defined for the compound of formula XIII;or the reaction optionally comprises(a-iii-2) reacting the compound of formula VI-1 with a compound offormula XIII-1 to give a compound of formula XII-1

wherein R¹ and R² are as defined for the compound of formula Ia and A′is as defined for the compound of formula XIII;and optionally(a-iv-2) reducing the compound of formula XII-1 with a suitable reducingagent to give a compound of formula XVI-1.In a further aspect the invention provides a compound of formula VI-1.In a further aspect the invention provides a compound of formula XXIX-1.In a further aspect the invention provides a compound of formula XXX-1.In a further aspect the invention provides a compound of formula XXXI-1.In a further aspect the invention provides a compound of formulaXXXII-1.In a further aspect the invention provides a compound of formulaXXXIII-1.

In the compounds above R¹ and R² are as defined for the compound offormula Ia.

In enantiomerically enriched mixtures of the invention, the molarproportion of the enriched compound in the mixture compared to the totalamount of both enantiomers is for example greater than 50%, e.g. atleast 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%.

Alkyl groups (either alone or as part of a larger group, such asalkoxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylcarbonyl- oralkoxycarbonyl-) can be in the form of a straight or branched chain andare, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl,2-methyl-prop-1-yl or 2-methyl-prop-2-yl. The alkyl groups are, unlessindicated to the contrary, preferably C₁-C₆, more preferably C₁-C₄, mostpreferably C₁-C₃ alkyl groups.

Alkylene groups can be in the form of a straight or branched chain andare, for example, —CH₂—, —CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—,—CH(CH₃)—CH₂—, or —CH(CH₂CH₃)—. The alkylene groups are, unlessindicated to the contrary, preferably C₁-C₆, more preferably C₁-C₃, morepreferably C₁-C₂, most preferably C₁ alkylene groups.

Alkenyl groups can be in the form of straight or branched chains, andcan be, where appropriate, of either the (E)- or (Z)-configuration.Examples are vinyl and allyl. The alkenyl groups are, unless indicatedto the contrary, preferably C₂-C₆, more preferably C₂-C₄, mostpreferably C₂-C₃ alkenyl groups.

Alkynyl groups can be in the form of straight or branched chains.Examples are ethynyl and propargyl. The alkynyl groups are, unlessindicated to the contrary, preferably C₂-C₆, more preferably C₂-C₄, mostpreferably C₂-C₃ alkynyl groups.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl groups (either alone or as part of a larger group, such ashaloalkoxy-, haloalkylthio-, haloalkylsulfinyl-, haloalkylsulfonyl-,haloalkylcarbonyl- or haloalkoxycarbonyl-) are alkyl groups which aresubstituted by one or more of the same or different halogen atoms andare, for example, difluoromethyl, trifluoromethyl, chlorodifluoromethylor 2,2,2-trifluoro-ethyl.

Haloalkenyl groups are alkenyl groups which are substituted by one ormore of the same or different halogen atoms and are, for example,2,2-difluoro-vinyl or 1,2-dichloro-2-fluoro-vinyl.

Haloalkynyl groups are alkynyl groups which are substituted by one ormore of the same or different halogen atoms and are, for example,1-chloro-prop-2-ynyl.

Cycloalkyl groups can be in mono- or bi-cyclic form and are, forexample, cyclopropyl, cyclobutyl, cyclohexyl andbicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups are, unless indicatedto the contrary, preferably C₃-C₈, more preferably C₃-C₆ cycloalkylgroups.

Aryl groups are aromatic ring systems which can be in mono-, bi- ortricyclic form. Examples of such rings include phenyl, naphthyl,anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyland naphthyl, phenyl being most preferred. Where an aryl moiety is saidto be substituted, the aryl moiety is, unless indicated to the contrary,preferably substituted by one to four substituents, most preferably byone to three substituents.

Heteroaryl groups are aromatic ring system containing at least oneheteroatom and consisting either of a single ring or of two or morefused rings. Preferably, single rings will contain up to threeheteroatoms and bicyclic systems up to four heteroatoms which willpreferably be chosen from nitrogen, oxygen and sulfur. Examples ofmonocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl andthiadiazolyl. Examples of bicyclic groups include quinolinyl,cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl,benzothiophenyl, benzothiazolyl and benzotriazolyl. Monocyclicheteroaryl groups are preferred, pyridyl being most preferred. Where aheteroaryl moiety is said to be substituted, the heteroaryl moiety is,unless indicated to the contrary, preferably substituted by one to foursubstituents, most preferably by one to three substituents.

Heterocyclyl groups are defined to include heteroaryl groups and inaddition their unsaturated or partially unsaturated analogues. Examplesof monocyclic groups include thietanyl, pyrrolidinyl, tetrahydrofuranyl,[1,3]dioxolanyl, piperidinyl, piperazinyl, [1,4]dioxanyl, andmorpholinyl or their oxidised versions such as 1-oxo-thietanyl and1,1-dioxo-thietanyl. Examples of bicyclic groups include2,3-dihydro-benzofuranyl, benzo[1,3]dioxolanyl, and2,3-dihydro-benzo[1,4]dioxinyl. Where a heterocyclyl moiety is said tobe substituted, the heterocyclyl moiety is, unless indicated to thecontrary, preferably substituted by one to four substituents, mostpreferably by one to three substituents.

Unless stated otherwise where groups are optionally substituted they maybe substituted e.g. by one to five groups, e.g. by one to three groups,preferably independently selected from nitro, cyano, hydroxy, halogen,mercapto, isocyano, cyanate, isothiocyanate, carboxy, carbamoyl,aminosulfonyl, monoalkylamino, dialkylamino, N-alkylcarbonylamino,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, SF₅, alkoxy,alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, alkoxy-carbonyl,alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, alkylthio,cycloalkylthio, alkenylthio, cycloalkenylthio, alkynylthio,alkylsulfenyl, alkylsulfinyl including isomers, alkylsulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylphosphinyl,alkylphosphonyl, alkylphosphinyl including isomers, alkylphosphonylincluding isomers, N-alkyl-aminocarbonyl, -dialkyl-aminocarbonyl,N-alkylcarbonyl-aminocarbonyl, N-alkylcarbonyl-N-alkylaminocarbonyl,aryl, aryloxy, benzyl, benzyloxy, benzylthio, arylthio, arylamino,benzylamino, trialkylsilyl, alkoxyalkyl, alkylthioalkyl,alkylthioalkoxy, alkoxyalkoxy, phenethyl, benzyloxy, haloalkyl,haloalkoxy, haloalkylthio, haloalkylcarbonyl, haloalkoxycarbonyl,haloalkoxyalkoxy, haloalkoxyalkylthio, haloalkoxyalkylcarbonyl orhaloalkoxyalkyl, cycloalkylamino-carbonyl, alkylsulfinylimino,alkylsulfonylimino, alkoxyimino, and a heterocyclic group;

preferably nitro, cyano, hydroxy, mercapto, isocyano, cyanate,isothiocyanate, carboxy, carbamoyl, aminosulfonyl,mono-C₁-C₁₂alkylamino, di-C₂-C₂₄alkylamino, N—C₁-C₁₂alkylcarbonylamino,C₁-C₁₂alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl,C₃-C₈cycloalkenyl, SF₅, C₁-C₁₂alkoxy, C₂-C₆alkenyloxy, C₂-C₆alkynyloxy,C₃-C₈cycloalkyloxy, C₃-C₈cycloalkenyloxy, C₁-C₁₂alkoxycarbonyl,C₂-C₆alkenyloxycarbonyl, C₂-C₆alkynyloxycarbonyl, aryloxycarbonyl,C₁-C₁₂alkylcarbonyl, C₂-C₆alkenylcarbonyl, C₂-C₆alkynylcarbonyl,arylcarbonyl, C₁-C₁₂alkylthio, C₃-C₈cycloalkylthio, C₂-C₆alkenylthio,C₃-C₈cycloalkenylthio, C₂-C₆alkynylthio, C₁-C₁₂alkylsulfenyl,C₁-C₁₂alkylsulfinyl including isomers, C₁-C₁₂alkylsulfonyl,mono-C₁-C₁₂alkylaminosulfonyl, di-C₂-C₂₄alkylaminosulfonyl,C₁-C₁₂alkylphosphinyl, C₁-C₁₂alkylphosphonyl, C₁-C₁₂alkylphosphinylincluding isomers, C₁-C₁₂alkylphosphonyl including isomers,N—C₁-C₁₂alkyl- aminocarbonyl, -di-C₂-C₂₄alkyl-aminocarbonyl,N—C₁-C₁₂alkylcarbonyl-aminocarbonyl,N—C₁-C₁₂alkylcarbonyl-N—C₁-C₁₂alkylaminocarbonyl, aryl, aryloxy, benzyl,benzyloxy, benzylthio, arylthio, arylamino, benzylamino, trialkylsilyl,C₁-C₁₂alkoxyalkyl, C₁-C₁₂alkylthioalkyl, C₁-C₁₂alkylthioalkoxy,C₁-C₁₂alkoxyalkoxy, phenethyl, benzyloxy, C₁-C₁₂haloalkyl,C₁-C₁₂haloalkoxy, C₁-C₁₂haloalkylthio, C₁-C₁₂haloalkylcarbonyl,C₁-C₁₂haloalkoxycarbonyl, C₁-C₁₂haloalkoxyalkoxy,C₁-C₁₂haloalkoxyC₁-C₁₂alkylthio, C₁-C₁₂haloalkoxyC₁-C₁₂alkylcarbonyl orC₁-C₁₂haloalkoxy-C₁-C₁₂alkyl, C₃-C₈cycloalkylamino-carbonyl,C₁-C₁₂alkylsulfinylimino, C₁-C₁₂alkylsulfonylimino, C₁-C₁₂alkoxyimino,and a heterocyclic group, wherein aryl is phenyl and heterocyclic groupsare heteroaryl groups as defined above. Preferred optional substituentsare cyano, halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, andC₁-C₄haloalkoxy.

Bearing in mind the stereocentre which is the subject of the invention,the invention otherwise includes all isomers of compounds of formula I,salts and N-oxides thereof, including enantiomers, diastereomers andtautomers. Tautomers of the compounds of formula I include the enamineform, for example. These are covered by the invention.

Preferred substituent values in compounds of formula I are as follows,which may be combined in any order. These preferred substituent valuesalso apply to other compounds of the invention in which the samesubstituents are present.

Preferably R¹ is trifluoromethyl.

Preferably R² is aryl or aryl substituted by one to five Q¹, orheteroaryl or heteroaryl substituted by one to five Q¹. Preferably R² isgroup A

wherein B¹, B², B³, B⁴ and Q¹ are as defined below. More preferably R²is group A1 or A2

More preferably R² is group A3 or A4

B¹, B², B³, B⁴ are independently C-Q¹ or nitrogen.

Q¹, Q², Q³, Q⁴, and Q⁵ are independently hydrogen, halogen, cyano,nitro, C₁-C₈alkyl, C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl,C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy, C₁-Cgalkylamino, C₁-C₈alkoxy,C₁-C₈haloalkoxy, mercapto, C₁-C₈alkylthio, C₁-C₈haloalkylthio,C₁-C₈alkylsulfinyl, C₁-C₈haloalkylsulfinyl, C₁-C₈alkylsulfonyl,C₁-C₈haloalkylsulfonyl, C₁-C₈alkylcarbonyl, C₁-C₈alkoxycarbonyl,optionally substituted aryl or optionally substituted heterocyclyl.Preferably, Q¹, Q², Q³, Q⁴, and Q⁵ are each independently hydrogen,halogen, cyano, C₁-C₈alkyl, C₁-C₈haloalkyl, C₁-C₈alkoxy orC₁-C₈haloalkoxy, more preferably bromo, chloro, fluoro, cyano, methyl,trifluoromethyl, methoxy or trifluoromethoxy, preferably bromo, chloroor trifluoromethyl. Preferably at least two of Q¹, Q², Q³, Q⁴, and Q⁵are not hydrogen.

When P is defined as hydroxy, alkoxy, aryloxy, alkylsulfinyl,arylsulfinyl or heteroaryl, each optionally substituted, and wherein theheteroaryl contains at least one ring nitrogen atom, and the heteroarylis connected at P via a ring nitrogen atom, then P is preferablyhydroxy, C₁-C₁₂alkoxy, C₁-C₁₂haloalkoxy phenyloxy, C₁-C₁₂sulfinyl,phenylsulfinyl or heteroaryl, wherein phenyl (including phenyloxy) andheteroaryl are optionally substituted by one to five groupsindependently selected from cyano, halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,C₁-C₄alkoxy, and C₁-C₄haloalkoxy, and heteroaryl is pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, isothiazolyl and thiadiazolyl, quinolinyl, cinnolinyl,quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl,benzothiazolyl or benzotriazolyl, more preferably P is hydroxyl,C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl,N-benzotriazolyl, or C₁-C₆alkylsulfinyl.

When P is defined as alkyl, aryl or heteroaryl, each optionallysubstituted (and e.g. wherein the heteroaryl is connected to at P via aring carbon atom), then preferably P is C₁-C₁₂alkyl, C₁-C₁₂haloalkyl,phenyl or heteroaryl, and heteroaryl is pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl and thiadiazolyl, quinolinyl, cinnolinyl, quinoxalinyl,indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl orbenzotriazolyl, e.g. wherein phenyl and heteroaryl are each optionallysubstituted by one to five groups independently selected from cyano,halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy and C₁-C₄haloalkoxy.

When P is defined as optionally substituted heteroaryl, and wherein theheteroaryl contains at least one ring nitrogen or oxygen atom, whereinthe heteroaryl is connected at P via a ring carbon atom, then preferablyP is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl, quinolinyl,cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl,benzothiophenyl, benzothiazolyl or benzotriazolyl, each optionallysubstituted by one to five groups independently selected from cyano,halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, and C₁-C₄haloalkoxy.

When P is defined as P is alkyl, hydroxy, alkoxy, aryloxy,alkylsulfinyl, or arylsulfinyl, each optionally substituted, thenpreferably P is C₁-C₁₂alkyl, C₁-C₁₂haloalkyl, hydroxy, C₁-C₁₂alkoxy,C₁-C₁₂haloalkoxy, phenyloxy, C₁-C₁₂sulfinyl, phenylsulfinyl, whereinphenyl is optionally substituted by one to five groups independentlyselected from cyano, halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,and C₁-C₄haloalkoxy.

Preferably A′ is selected from P1 to P6

In one group of compounds A′ is P1. In another group of compounds A′ isP2. In another group of compounds A′ is P3. In another group ofcompounds A′ is P4. In another group of compounds A′ is P5. In anothergroup of compounds A′ is P6. In another group of compounds A′ isselected from P3 to P5. When P is P2 to P5, P is preferably P7 to P22

A¹, A² and A³ are independently of each other C—H, C—R⁵, or nitrogen.Preferably no more than two of A¹, A² and A³ are nitrogen. In one groupof compounds A¹, A² and A³ are each C—R⁵. In one group of compounds A¹is nitrogen and A² and A³ are both C—R⁵. In another group of compoundsA² is nitrogen and A¹ and A³ are both C—R⁵. In another group ofcompounds A¹ and A² are both nitrogen and A³ is C—R⁵. In one group ofcompounds A¹, A² and A³ are each C—H. In one group of compounds A¹ isnitrogen and A² and A³ are both C—H. In another group of compounds A² isnitrogen and A¹ and A³ are both C—H. In another group of compounds A¹and A² are both nitrogen and A³ is C—H. Preferably A¹, A² and A³ areeach C—H.

A^(1′), A^(2′), A^(3′), A^(4′), A^(5′) and A^(6′) are independently ofeach other C—H, C—R⁵ or nitrogen provided that no more than two ofA^(1′), A^(2′), A^(3′), A^(4′), A^(5′) and A^(6′) are nitrogen.Preferably A^(1′), A^(2′), A^(3′), A^(4′), A^(5′) and A^(6′) are C—H.

The ring formed by A¹, A², and A³, or A^(1′), A^(2′), A^(3′), A^(4′),A^(5′) and A^(6′) may, for example, be phenyl, pyridyl, pyrimidine,pyrazine, pyridazine, naphthyl or quinoline.

Each R⁵ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl,C₂-C₈haloalkynyl, C₃-C₁₀cycloalkyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy,C₁-C₈alkylthio, C₁-C₈haloalkylthio, C₁-C₈alkylsulfinyl,C₁-C₈haloalkylsulfinyl, C₁-C₈alkylsulfonyl or C₁-C₈haloalkylsulfonyl.Preferably, each R⁵ is independently halogen, C₁-C₈alkyl, C₁-C₈haloalkylor C₂-C₈alkenyl. More preferably, each R⁵ is independently bromo,chloro, fluoro, methyl, trifluoromethyl or vinyl, most preferably eachR⁵ is methyl.

Q is hydrogen, halogen, nitro, NH₂, cyano, C₁-C₈alkyl, C₁-C₈haloalkyl,C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₃-C₈haloalkynyl,C₃-C₁₀cycloalkyl, C₁-C₈alkylthio, C₁-C₈haloalkylthio,C₁-C₈alkylsulfinyl, C₁-C₈haloalkylsulfinyl, C₁-C₈alkylsulfonyl,C₁-C₈haloalkylsulfonyl, arylsulfonyl or arylsulfonyl substituted by oneto five groups independently selected from C₁-C₄alkyl and nitro,—N(R⁶)R^(7b), —C(W⁵)N(R⁶)R⁷, —C(R¹⁵)(R¹⁶)N(R¹⁷)R¹⁸, C(═W⁵)OR^(7a),—C(═W⁵)R¹³, —OR¹⁴, aryl or aryl substituted by one to five Z¹,heterocyclyl or heterocyclyl substituted by one to five Z¹. Preferably,Q is cyano, halogen, nitro, NH₂, arylsulfonyl or arylsulfonylsubstituted by one to five groups independently selected from C₁-C₄alkyland nitro, heterocyclyl or heterocyclyl substituted by one to five Z¹,—OR¹⁴, —C(═O)N(R⁶)R⁷, —CO(═O)R^(7a), —C(═O)R¹³, or—C(R¹⁵)(R¹⁶)N(R¹⁷)R¹⁸. More preferably, Q is cyano, halogen, nitro, NH₂,phenylsulfonyl or phenylsulfonyl substituted by one to five groupsindependently selected from C₁-C₄alkyl and nitro, —OR¹⁴, —C(═O)N(R⁶)R⁷,—CO(═O)R^(7a), —C(═O)R¹³, —C(R¹⁵)(R¹⁶)N(R¹⁷)R¹⁸, or a heterocycleselected from H1 to H9

Even more preferably, Q is cyano, halogen, nitro, NH₂, C₁-C₈alkoxy,phenylsulfonyl or phenylsulfonyl substituted by one to five groupsindependently selected from C₁-C₄ alkyl and nitro, —C(═O)N(R⁶)R⁷,—CO(═O)R^(7a), —C(═O)R¹³, —C(R¹⁵)(R¹⁶)N(R¹⁷)R¹⁸, or a heterocycleselected from H1 to H9.

k is 0, 1, or 2, preferably 0.

R⁶ is hydrogen, C₁-C₈alkyl, C₁-C₈alkoxy, C₂-C₈alkenyl, C₂-C₈alkynyl,C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkyl-C₁-C₄alkylene, C₁-C₈alkylcarbonyl orC₁-C₈alkoxycarbonyl. Preferably, R⁶ is hydrogen, C₁-C₈alkyl,C₁-C₈alkoxy, C₁-C₈alkylcarbonyl, or C₁-C₈alkoxycarbonyl. Morepreferably, R⁶ is hydrogen, methyl, ethyl, methylcarbonyl ormethoxycarbonyl, more preferably hydrogen, methyl or ethyl, mostpreferably hydrogen.

R⁷ is hydrogen, alkyl or alkyl substituted by one to five R⁸, alkenyl oralkenyl substituted by one to five R⁸, alkynyl or alkynyl substituted byone to five R⁸, C₃-C₁₀cycloalkyl or C₃-C₁₀cycloalkyl substituted by oneto five R⁹, C₃-C₁₀cycloalkyl-C₁-C₄alkylene orC₃-C₁₀cycloalkyl-C₁-C₄alkylene wherein the cycloalkyl moiety issubstituted by one to five R⁹, C₁-C₈alkyl-N(R⁶)—C(═O)—C₁-C₄alkylene,C₁-C₈haloalkyl-N(R⁶)—C(═O)—C₁-C₄alkylene,C₃-C₈cycloalkyl-aminocarbonyl-C₁-C₄alkylene, C₁-C₆alkyl-O—N═CH—,C₁-C₆haloalkyl-O—N═CH—, aryl-C₁-C₆alkylene or aryl-C₁-C₆alkylene whereinthe aryl moiety is substituted by one to five R¹⁰,heterocyclyl-C₁-C₆alkylene or heterocyclyl-C₁-C₆alkylene wherein theheterocyclyl moiety is substituted by one to five R¹⁰ and wherein eachheterocyclyl moiety contains one or more ring members independentlyselected from O, N, C═O, C═N—OR¹², N—R¹², S, SO, SO₂, S═N—R¹² andSO═N—R¹², aryl or aryl substituted by one to five R¹⁰, heterocyclyl orheterocyclyl substituted by one to five R¹⁰ and wherein eachheterocyclyl moiety contains one or more ring members independentlyselected from O, N, C═O, C═N—OR¹², N—R¹², S, SO, SO₂, S═N—R¹² andSO═N—R¹². Preferably, R⁷ is hydrogen, C₁-C₅alkyl or C₁-C₅alkylsubstituted by one to five R⁸, C₃-C₁₀cycloalkyl or C₃-C₁₀cycloalkylsubstituted by one to five R⁹, aryl-C₁-C₆alkylene or aryl-C₁-C₆alkylenewherein the aryl moiety is substituted by one to five R¹⁰,heterocyclyl-C₁-C₆alkylene or heterocyclyl-C₁-C₆alkylene wherein theheterocyclyl moiety is substituted by one to five R¹⁰ and wherein eachheterocyclyl moiety contains one or more ring members independentlyselected from O, N, C═O, C═N—OR¹², N—R¹², S, SO, SO₂, S═N—R¹² andSO═N—R¹², aryl or aryl substituted by one to five R¹⁰, heterocyclyl orheterocyclyl substituted by one to five R¹⁰ and wherein eachheterocyclyl moiety contains one or more ring members independentlyselected from O, N, C═O, C═N—OR¹², N—R¹², S, SO, SO₂, S═N—R¹² andSO═N—R¹², C₁-C₈alkyl-N(R⁶)—C(═O)—C₁-C₄ alkylene,C₁-C₈haloalkyl-N(R⁶)—C(═O)—C₁-C₄alkylene,C₃-C₈cycloalkylaminocarbonyl-C₁-C₄alkylene, C₁-C₆alkyl-O—N═CH—, orC₁-C₆haloalkyl-O—N═CH—. More preferably, R⁷ is hydrogen, C₁-C₈alkyl,C₁-C₈haloalkyl, phenyl-C₁-C₆alkylene or phenyl-C₁-C₆alkylene wherein thephenyl moiety is substituted by one to five R¹⁰, pyridyl-C₁-C₆alkyleneor pyridyl-C₁-C₆alkylene wherein the pyridyl moiety is substituted byone to four R¹⁰, thiazolyl-C₁-C₆alkylene or thiazolyl-C₁-C₆alkylenewherein the thiazolyl moiety is substituted by one or two R¹⁰, phenyl orphenyl substituted by one to five R¹⁰, pyridyl or pyridyl substituted byone to four R¹⁰, thiazolyl or thiazolyl substituted by one or two R¹⁰,C₃-C₆cycloalkyl or C₃-C₆cycloalkyl wherein one ring atom is replaced byO or S, C₁- C₄alkyl-O—N═CH—, C₁-C₄haloalkyl-O—N═CH—,C₁-C₄alkyl-N(R⁶)—C(═O)—CH₂—, C₁-C₄haloalkyl-N(R⁶)—C(═O)—CH₂—, or a groupof formula (Y)

In one group of compounds R⁷ is not a group of formula (Y)

L is a single bond or C₁-C₆alkylene;

Y¹, Y² and Y³ are independently of another O, CR²¹R²², C═O, C═N—OR¹²,N—R¹², S, SO, SO₂, S═N—R¹² or SO═N—R¹², provided that at least one ofY¹, Y² or Y³ is not CR²¹R²², C═O or C═N—OR¹². In the group of formula(Y), preferably two of Y¹, Y² and Y³ are CR²¹⁻²², x and the other is O,N—R¹², S, SO, SO₂, S═N—R¹² or SO═N—R¹², more preferably two of Y¹, Y²and Y³ are CH₂ and the other is S, SO or SO₂. When L is a bond Y¹ and Y³are preferably CH₂ and Y² is S, SO, SO₂, S═N—R¹² or SO═N—R¹². When L isalkylene, Y¹ is preferably S, SO, SO₂, S═N—R¹² or SO═N—R¹² and Y² and Y³are CH₂.

R^(7a) is hydrogen, alkyl or alkyl substituted by one to five R⁸,alkenyl or alkenyl substituted by one to five R⁸, alkynyl or alkynylsubstituted by one to five R⁸, cycloalkyl or cycloalkyl substituted byone to five R⁹, aryl-alkylene or aryl-alkylene wherein the aryl moietyis substituted by one to five R¹⁰, heteroaryl-alkylene orheteroaryl-alkylene wherein the heteroaryl moiety is substituted by oneto five R¹⁰, aryl or aryl substituted by one to five R¹⁰, or heteroarylor heteroaryl substituted by one to five R¹⁰. Preferably, R^(7a) ishydrogen, C₁-C₁₅alkyl or C₁-C₁₅alkyl substituted by one to five R⁸,C₂-C₁₅alkenyl or C₂-C₁₅alkenyl substituted by one to five R⁸,C₂-C₁₅alkynyl or C₂-C₁₅alkynyl substituted by one to five R⁸,C₃-C₁₀cycloalkyl or C₃-C₁₀cycloalkyl substituted by one to five R⁹,aryl-C₁- C₆alkylene or aryl-C₁-C₆alkylene wherein the aryl moiety issubstituted by one to five R¹⁰, heteroaryl-C₁-C₆alkylene orheteroaryl-C₁-C₆alkylene wherein the heteroaryl moiety is substituted byone to five R¹⁰, or heteroaryl or heteroaryl substituted by one to fiveR¹⁰. More preferably R^(7a) is hydrogen, C₁-C₁₅alkyl, C₁-C₁₅haloalkylC₂-C₁₅alkenyl, C₂-C₁₅haloalkenyl, C₂-C₁₅alkynyl, C₂-C₁₅haloalkynyl,phenyl-C₁-C₄alkylene or phenyl-C₁-C₄alkylene wherein the phenyl moietyis substituted by one to five halogen, pyridyl-C₁-C₄alkyl orpyridyl-C₁-C₄alkyl wherein the pyridyl moiety is substituted by one tofour halogen, pyridyl or pyridyl substituted by one to four R¹⁰, mostpreferably R^(7a) is C₁-C₁₅alkyl, C₁-C₁₅haloalkyl, C₂-C₁₅alkenyl,C₂-C₁₅haloalkenyl, pyridyl or benzyl.

R^(7b) is hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl cycloalkyl, halocycloalkyl, alkylcarbonyl,haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, or benzyl, morepreferably R^(7b) is hydrogen, C₁-C₁₅alkyl, C₁-C₁₅haloalkyl,C₂-C₁₅alkenyl, C₂-C₁₅haloalkenyl, C₂-C₁₅alkynyl, C₂-C₁₅haloalkynyl,C₃-C₁₀cycloalkyl, C₁-C₁₅alkylcarbonyl or C₁-C₁₅alkoxycarbonyl; mostpreferably R^(7b) is C₁-C₁₅alkyl, C₁-C₁₅haloalkyl, C₂-C₁₅ alkenyl orC₂-C₁₅haloalkenyl.

Each R⁸ is independently halogen, cyano, nitro, hydroxy, NH₂, mercapto,C₁-C₈alkyl, C₁-C₈haloalkyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy,C₁-C₈alkylthio, C₁-C₈haloalkylthio, C₁-C₈alkylsulfinyl,C₁-C₈haloalkylsulfinyl, C₁-C₈alkylsulfonyl, C₁-C₈haloalkylsulfonyl,C₁-C₈alkylamino, C₂-C₈dialkylamino, C₃-C₈cycloalkylamino,C₁-C₈alkylcarbonyl, C₁-C₈alkoxycarbonyl, C₁-C₈alkylaminocarbonyl,C₁-C₈dialkylaminocarbonyl, C₁-C₈haloalkylcarbonyl,C₁-C₈haloalkoxycarbonyl, C₁-C₈haloalkylaminocarbonyl,C₁-C₈halodialkylaminocarbonyl. Preferably, each R⁸ is independentlyhalogen, cyano, nitro, hydroxy, C₁-C₈alkoxy, C₁-C₈haloalkoxy,C₁-C₈alkylcarbonyl, C₁-C₈alkoxycarbonyl, mercapto, C₁-C₈alkylthio,C₁-C₈haloalkylthio, C₁-C₈alkylsulfinyl, C₁-C₈haloalkylsulfinyl,C₁-C₈alkylsulfonyl. More preferably, each R⁸ is independently halogen,cyano, nitro, hydroxy, C₁-C₈alkoxy, C₁-C₈haloalkoxy, mercapto,C₁-C₈alkylthio, C₁-C₈haloalkylthio, more preferably bromo, chloro,fluoro, methoxy, or methylthio, most preferably chloro, fluoro, ormethoxy.

Each R⁹ is independently halogen or C₁-C₈alkyl. Preferably, each R⁹ isindependently chloro, fluoro or methyl, most preferably each R⁹ methyl.

Each R¹⁰ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl,C₂-C₈haloalkynyl, hydroxy, C₁-C₈alkoxy, C₁-C₈haloalkoxy, mercapto,C₁-C₈alkylthio, C₁-C₈haloalkylthio, C₁-C₈alkylsulfinyl,C₁-C₈haloalkylsulfinyl, C₁-C₈alkylsulfonyl, C₁-C₈haloalkylsulfonyl,C₁-C₈alkylcarbonyl, C₁-C₈alkoxycarbonyl, aryl or aryl substituted by oneto five R¹¹, or heterocyclyl or heterocyclyl substituted by one to fiveR¹¹. Preferably each R¹⁰ is independently halogen, cyano, nitro,C₁-C₈alkyl, C₁-C₈haloalkyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy, morepreferably bromo, chloro, fluoro, cyano, nitro, methyl, ethyl,trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, mostpreferably bromo, chloro, fluoro, cyano or methyl.

Each R⁴ and R¹¹ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy or C₁-C₈alkoxycarbonyl;more preferably each R⁴ and R¹¹ is independently bromo, chloro, fluoro,cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxyor trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro ormethyl, most preferably each R⁴ and R¹¹ is independently chloro, fluoroor methyl.

Each R¹² is independently hydrogen, cyano, cyano-C₁-C₈alkyl, C₁-C₈alkyl,C₁-C₈haloalkyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkyl where one carbon atomis replaced by O, S, S(O) or SO₂, or C₃-C₈cycloalkyl-C₁-C₈alkylene,C₃-C₈cycloalkyl-C₁-C₈alkylene where one carbon atom in the cycloalkylgroup is replaced by O, S, S(O) or SO₂, orC₃-C₈cycloalkyl-C₁-C₈haloalkylene, C₁-C₈hydroxyalkyl,C₁-C₈alkoxy-C₁-C₈alkylene, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl,C₂-C₈haloalkynyl, aryl or aryl substituted by one to three R¹¹,C₁-C₈alkylcarbonyl, C₁-C₈haloalkylcarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈haloalkoxycarbonyl, C₁-C₈alkylsulfonyl, C₁-C₈haloalkylsulfonyl,aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene where the aryl moiety issubstituted by one to three R¹¹, or heteroaryl-C₁-C₄alkylene orheteroaryl-C₁-C₄alkylene where the heteroaryl moiety is substituted byone to three R¹¹, or C₁-C₄alkyl-C₁-C₄alkyl-O—N═)C—CH₂—. Preferably, eachR¹² is independently hydrogen, cyano, C₁-C₈alkyl, C₁-C₈haloalkyl,C₁-C₈alkylcarbonyl, C₁-C₈haloalkylcarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈haloalkoxycarbonyl, C₁-C₈alkylsulfonyl, C₁-C₈haloalkylsulfonyl,aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene where the aryl moiety issubstituted by one to three R¹¹, or heteroaryl-C₁-C₄alkylene orheteroaryl-C₁-C₄alkylene where the heteroaryl moiety is substituted byone to three R¹¹. More preferably, each R¹² is independently hydrogen,cyano, C₁-C₈alkyl, C₁-C₈haloalkyl, C₁-C₈alkylcarbonyl,C₁-C₈haloalkylcarbonyl, C₁-C₈alkoxycarbonyl, C₁-C₈haloalkoxycarbonyl,C₁-C₈alkylsulfonyl, C₁-C₈haloalkylsulfonyl, phenyl-C₁-C₄alkylene orphenyl-C₁-C₄alkylene where the phenyl moiety is substituted by one tothree R¹¹, or pyridyl-C₁-C₄alkylene or pyridyl-C₁-C₄alkylene where thepyridyl moiety is substituted by one to three R¹¹.

R¹³ is halogen or imidazole, preferably chloro, fluoro or bromo.

Each R¹⁴ is independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl,C₂-C₈alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkyl-C₃-C₈cycloalkyl,C₃-C₈cycloalkyl-C₁-C₆alkylene, C₁-C₁₀alkylcarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈alkylsulfonyl, C₁-C₈haloalkylsulfonyl, or arylsulfonyl orarylsulfonyl substituted by one to five groups independently selectedfrom C₁-C₄alkyl and nitro; more preferably each R¹⁴ is independentlyhydrogen, C₁-C₈alkyl, phenylsulfonyl or phenylsulfonyl substituted byone to five groups independently selected from C₁-C₄alkyl and nitro.

R¹⁵ and R¹⁶ are each independently hydrogen, C₁-C₁₂alkyl or C₁-C₁₂alkylsubstituted by one to five R⁸, C₃-C₈cycloalkyl or C₃-C₈cycloalkylsubstituted by one to five R⁹, C₂-C₁₂alkenyl or C₂-C₁₂alkenylsubstituted by one to five R⁸, C₂-C₁₂alkynyl or C₂-C₁₂alkynylsubstituted by one to five R⁸, cyano, C₁-C₁₂alkoxycarbonyl orC₁-C₁₂alkoxycarbonyl substituted by one to five R⁸,C₁-C₁₂alkoxythiocarbonyl or C₁-C₁₂alkoxythiocarbonyl substituted by oneto five R⁸, or R¹⁵ and R¹⁶ together with the carbon atom to which theyare attached may form a 3 to 6-membered carbocyclic ring. Preferably,R¹⁵ and R¹⁶ are each independently hydrogen, C₁-C₁ alkyl,C₁-C₁₂haloalkyl, C₃-C₈cycloalkyl, C₃-C₈halocycloalkyl, C₂-C₁₂alkenyl orC₂-C₁₂haloalkenyl, C₂-C₁₂alkynyl, C₂-C₁₂haloalkynyl cyano,C₁-C₁₂alkoxycarbonyl, C₁-C₁₂haloalkoxycarbonyl,C₁-C₁₂alkoxythiocarbonyl, C₁-C₁₂haloalkoxythiocarbonyl, or R¹⁵ and R¹⁶together with the carbon atom to which they are attached may form a 3 to6-membered carbocyclic ring. Preferably, R¹⁵ and R¹⁶ are eachindependently hydrogen, halogen, cyano, C₁-C₄alkyl or C₁-C₄haloalkyl.

R¹⁷ is hydrogen, NH₂, hydroxyl, C₁-C₁₂ alkoxy or C₁-C₁₂alkoxysubstituted by one to five R⁸, C₁-C₁₂alkylcarbonylamino orC₁-C₁₂alkylcarbonylamino wherein the alkyl is substituted by one to fiveR⁸, C₁-C₁₂alkylamino or C₁-C₁₂alkylamino wherein the alkyl issubstituted by one to five R⁸, C₁-C₁₂alkyl or C₁-C₁₂alkyl substituted byone to five R⁸, C₃-C₈cycloalkyl or C₃-C₈cycloalkyl substituted by one tofive R⁹, cyano, C₂-C₁₂alkenyl or C₂-C₁₂alkenyl substituted by one tofive R⁸, C₂-C₁₂alkynyl or C₂-C₁₂alkynyl substituted by one to five R⁸,C₁-C₁₂alkylcarbonyl or C₁-C₁₂alkylcarbonyl substituted by one to fiveR⁸, C₁-C₁₂alkoxycarbonyl or C₁-C₁₂alkoxycarbonyl substituted by one tofive R⁸ or is selected from CH₂—R²⁵, C(═O)R¹⁹ and C(═S)R¹⁹. Preferably,R¹⁷ is hydrogen, NH₂, hydroxyl, C₁-C₁₂alkoxy, C₁-C₁₂haloalkoxy,C₁-C₁₂alkylcarbonylamino, C₁-C₁₂haloalkylcarbonylamino,C₁-C₁₂alkylamino, C₁-C₁₂haloalkylamino, C₁-C₁₂alkyl, C₁-C₁₂haloalkyl,C₃- C₈cycloalkyl, C₃-C₈halocycloalkyl, cyano, C₁-C₁₂alkenyl,C₁-C₁₂haloalkenyl, C₂-C₁₂alkynyl, C₂-C₁₂haloalkynyl,C₁-C₁₂alkylcarbonyl, C₁-C₁₂haloalkylcarbonyl, C₁-C₈alkoxycarbonyl, orC₁-C₈haloalkoxycarbonyl. More preferably, R¹⁷ is hydrogen, C₁-C₈alkyl,C₁-C₈alkoxy, C₁-C₈alkylcarbonyl, or C₁-C₈alkoxycarbonyl.

R¹⁸ is hydrogen, cyano, carbonyl, thiocarbonyl, C₁-C₁₂alkylcarbonyl orC₁-C₁₂ alkylcarbonyl substituted by one to five R⁸,C₁-C₁₂alkylthiocarbonyl or C₁-C₁₂alkylthiocarbonyl substituted by one tofive R⁸, C₁-C₁₂alkylaminocarbonyl or C₁-C₁₂alkylaminocarbonyl whereinthe alkyl is substituted by one to five R⁸, C₁-C₁₂alkylaminothiocarbonylor C₁-C₁₂alkylaminothiocarbonyl wherein the alkyl is substituted by oneto five R⁸, C₂-C₂₄ (total carbon number) dialkylaminocarbonyl or C₂-C₂₄(total carbon number) dialkylaminocarbonyl wherein one or both alkyl issubstituted by one to five R⁸, C₂-C₂₄ (total carbon number)dialkylaminothiocarbonyl or C₂-C₂₄ (total carbon number)dialkylaminothiocarbonyl wherein one or both alkyl is substituted by oneto five R⁸, C₁-C₁₂alkoxyaminocarbonyl or C₁-C₁₂alkoxyaminocarbonylwherein the alkoxy is substituted by one to five R⁸,C₁-C₁₂alkoxyaminothiocarbonyl or C₁-C₁₂alkoxyaminothiocarbonyl whereinthe alkoxy is substituted by one to five R⁸, C₁-C₁₂alkoxycarbonyl orC₁-C₁₂alkoxycarbonyl substituted by one to five R⁸,C₁-C₁₂alkoxythiocarbonyl or C₁-C₁₂alkoxythiocarbonyl substituted by oneto five R⁸, C₁-C₁₂thioalkoxycarbonyl or C₁-C₁₂thioalkoxycarbonylsubstituted by one to five R⁸, C₁-C₁₂thioalkoxythiocarbonyl orC₁-C₁₂thioalkoxythiocarbonyl substituted by one to five R⁸,C₁-C₁₂alkylsulfonyl or C₁-C₁₂alkylsulfonyl substituted by one to fiveR⁸, C₃-C₁₂cycloalkylcarbonyl or C₃-C₁₂cycloalkylcarbonyl substituted byone to five R⁹, C₂-C₁₂alkenylcarbonyl or C₂-C₁₂alkenylcarbonylsubstituted by one to five R⁸, C₂-C₁₂alkynylcarbonyl orC₂-C₁₂alkynylcarbonyl substituted by one to five R⁸,C₃-C₁₂cycloalkyl-C₁-C₁₂alkylcarbonyl orC₃-C₁₂cycloalkyl-C₁-C₁₂alkylcarbonyl substituted by one to five R⁹,C₁-C₁₂alkylsulfenyl-C₁-C₁₂alkylcarbonyl orC₁-C₁₂alkylsulfenyl-C₁-C₁₂alkylcarbonyl substituted by one to five R⁸,C₁-C₁₂alkylsulfinyl-C₁-C₁₂alkylcarbonyl orC₁-C₁₂alkylsulfinyl-C₁-C₁₂alkylcarbonyl substituted by one to five R⁸,C₁-C₁₂ alkylsulfonyl-C₁-C₁₂alkylcarbonyl orC₁-C₁₂alkylsulfonyl-C₁-C₁₂alkylcarbonyl substituted by one to five R⁸,C₁-C₁₂alkylcarbonyl-C₁-C₁₂alkylcarbonyl orC₁-C₁₂alkylcarbonyl-C₁-C₁₂alkylcarbonyl substituted by one to five R⁸,C₃-C₁₂cycloalkylaminocarbonyl or C₃-C₁₂cycloalkylaminocarbonyl whereinthe cycloalkyl is substituted by one to five R⁹,C₂-C₁₂alkenylaminocarbonyl or C₂-C₁₂alkenylaminocarbonyl wherein thealkenyl is substituted by one to five R⁸, C₂-C₁₂alkynylaminocarbonyl orC₂-C₁₂alkynylaminocarbonyl wherein the alkynyl is substituted by one tofive R⁸, or is selected from C(═O)R¹⁹ and C(═S)R¹⁹. Preferably R¹⁸ ishydrogen, cyano, carbonyl, thiocarbonyl, C₁-C₁₂alkylcarbonyl,C₁-C₁₂haloalkylcarbonyl, C₁-C₁₂alkylthiocarbonyl,C₁-C₁₂haloalkylthiocarbonyl, C₁-C₁₂alkylaminocarbonyl,C₁-C₁₂alkylaminothiocarbonyl, C₂-C₂₄ (total carbon number)dialkylaminocarbonyl, C₂-C₂₄ (total carbon number)dialkylaminothiocarbonyl, C₁-C₁₂alkoxyaminocarbonyl,C₁-C₁₂alkoxyaminothiocarbonyl, C₁-C₁₂alkoxycarbonyl,C₁-C₁₂haloalkoxycarbonyl, C₁-C₁₂alkoxythiocarbonyl,C₁-C₁₂haloalkoxythiocarbonyl, C₁-C₁₂thioalkoxycarbonyl,C₁-C₁₂thioalkoxythiocarbonyl, C₁- C₁₂alkylsulfonyl,C₁-C₁₂haloalkylsulfonyl, C₃-C₁₂cycloalkylcarbonyl,C₃-C₁₂halocycloalkylcarbonyl, C₂-C₁₂alkenylcarbonyl,C₂-C₁₂haloalkenylcarbonyl, C₂-C₁₂ alkynylcarbonyl,C₂-C₁₂haloalkynylcarbonyl, C₃-C₁₂cycloalkyl-C₁-C₁₂alkylcarbonyl,C₃-C₁₂halocycloalkyl-C₁-C₁₂alkylcarbonyl,C₂-C₁₂alkylsulfenyl-C₁-C₁₂alkylcarbonyl,C₂-C₁₂haloalkylsulfenyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂alkylsulfinyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂haloalkylsulfinyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂alkylsulfonyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂haloalkylsulfonyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂alkylcarbonyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂haloalkylcarbonyl-C₁-C₁₂alkylcarbonyl,C₃-C₁₂cycloalkylaminocarbonyl, C₂-C₁₂alkenylaminocarbonyl,C₂-C₁₂alkynylaminocarbonyl. More preferably, R¹⁸ is C₁-C₄alkylcarbonylor C₁-C₄alkylcarbonyl substituted by one to five R⁸, C₃-C₆cycloalkylcarbonyl or C₃-C₆cycloalkylcarbonyl wherein the cycloalkyl issubstituted by one to five R⁹; even more Preferably, R¹⁸ isC₁-C₄alkylcarbonyl, C₁-C₄haloalkylcarbonyl, C₃-C₆cycloalkylcarbonyl orC₃-C₆halocycloalkylcarbonyl.

R¹⁷ and R¹⁸ together with the nitrogen atom to which they are bound mayform a 3- to 6-membered heterocyclic ring which may be substituted byone to five R¹¹, or may be substituted with a keto, thioketo ornitroimino group.

R¹⁹ is aryl or aryl substituted by one to five R¹¹, heterocyclyl orheterocyclyl substituted by one to five R¹¹. The aryl is preferablyphenyl and the heterocyclyl is preferably pyridyl.

R²⁰ is hydrogen or C₁-C₅alkyl.

Each R²¹ and R²² is independently hydrogen, halogen, C₁-C₅alkyl orC₁-C₈haloalkyl.

Each Z¹ is independently halogen, C₁-C₁₂alkyl or C₁-C₁₂alkyl substitutedby one to five R⁸, nitro, C₁-C₁₂alkoxy or C₁-C₁₂alkoxy substituted byone to five R⁸, cyano, C₁-C₁₂alkylsulfinyl, C₁-C₁₂ alkylsulfonyl,C₁-C₁₂haloalkylsulfinyl, C₁-C₁₂haloalkylsulfonyl, hydroxyl or thiol.

Preferably each Z¹ is independently halogen, cyano, C₁-C₄alkyl,C₁-C₄haloalkyl, C₁-C₄alkoxy, or C₁-C₄haloalkoxy, more preferably each Z¹is independently hydrogen, halogen, methyl, halomethyl, methoxy orhalomethoxy.

R²⁶ is hydrogen, azido, halogen, hydroxy, optionally substituted amino,optionally substituted alkoxy, optionally substituted alkoxycarbonyl or—CO₂H, more preferably —N(R²⁸)(R²⁹), halogen, hydroxy, C₁-C₈alkoxy,C₁-C₈haloalkoxy, C₁-C₈alkoxycarbonyl, C₁-C₈haloalkoxycarbonyl, or —CO₂H.

R²⁷ is hydrogen, halogen, hydroxy, optionally substituted amino,optionally substituted alkyl, optionally substituted alkoxy, optionallysubstituted aloxycarbonyl, more preferably hydrogen, halogen, hydroxy,hydrogen, C₁-C₈alkyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy, more preferablyhydrogen, C₁-C₈alkyl, C₁-C₈alkoxy, or C₁-C₈haloalkoxy.

R²⁶ and R²⁷ may together be oxo, optionally substituted oxime,optionally substituted imine and optionally substituted hydrazone

R²⁸ is hydrogen, cyano, formyl, thioformyl, alkylcarbonyl,haloalkylcarbonyl, alkyl-thiocarbonyl, haloalkyl-thiocarbonyl, mono- ordi-alkylaminocarbonyl, mono- or di-alkylamino-thiocarbonyl,alkoxyaminocarbonyl, alkoxyamino-thiocarbonyl, alkoxycarbonyl,alkoxyalkylcarbonyl, alkoxy-thiocarbonyl, alkylthio-carbonyl,alkylthio-thiocarbonyl, alkylsulfonyl, haloalkylsulfonyl,cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkynylalkylcarbonyl, cycloalkyl-alkylcarbonyl, alkylthioalkyl-carbonyl,alkylsulfinylalkylcarbonyl, alkylsulfonylalkylcarbonyl,alkylcarbonylalkylcarbonyl, cycloalkylaminocarbonyl,alkenylaminocarbonyl, alkynylaminocarbonyl, —CH₂—R³⁰, —C(O)R³⁰ or—C(S)R³⁰, and each group from alkylcarbonyl to alkynylaminocarbonylamong the definitions of R⁸ may be substituted; preferably R²⁸ ishydrogen, cyano, formyl, thioformyl, C₁-C₁₂alkylcarbonyl,C₁-C₁₂haloalkyl-carbonyl, C₁-C₁₂alkyl-thiocarbonyl,C₁-C₁₂haloalkyl-thiocarbonyl, mono-C₁-C₁₂ ordi-C₂-C₂₄alkyl-aminocarbonyl, mono-C₁-C₁₂ ordi-C₂-C₂₄alkylamino-thiocarbonyl, C₁-C₁₂alkoxy-aminocarbonyl,C₁-C₁₂alkoxyamino-thiocarbonyl, C₁-C₁₂alkoxy-carbonyl,C₁-C₁₂alkoxy-C₁-C₁₂alkyl-carbonyl, C₁-C₁₂alkoxy-thiocarbonyl,C₁-C₁₂alkylthio-carbonyl, C₁-C₁₂alkylthio-thiocarbonyl,C₁-C₁₂alkylsulfonyl, C₁-C₁₂haloalkylsulfonyl, C₃-C₈cycloalkyl-carbonyl,C₂-C₆alkenyl-carbonyl, C₂-C₆alkynyl-carbonyl,C₂-C₆alkynyl-C₁-C₁₂alkyl-carbonyl, C₃-C₈cycloalkyl-C₁-C₁₂alkyl-carbonyl,C₁-C₁₂alkylthio-C₁-C₁₂alkyl-carbonyl,C₁-C₁₂alkyl-sulfinyl-C₁-C₁₂alkyl-carbonyl,C₁-C₁₂alkylsulfonyl-C₁-C₁₂alkyl-carbonyl,C₁-C₁₂alkylcarbonyl-C₁-C₁₂alkyl-carbonyl, C₃-C₈cycloalkylamino-carbonyl,C₂-C₆alkenylamino-carbonyl, C₂-C₆alkynylamino-carbonyl, —CH₂—R¹⁰,—C(O)R¹⁰, or —C(S)R¹⁰, and each group from C₁-C₁₂alkyl-carbonyl toC₂-C₆alkynyl-amino-carbonyl, among the definitions of R⁸ may beoptionally substituted; more preferably R²⁸ is hydrogen, cyano,carbonyl, thiocarbonyl, C₁-C₆alkyl-carbonyl, C₁-C₆haloalkyl-carbonyl,C₁-C₆alkyl-thiocarbonyl, C₁-C₆haloalkyl-thiocarbonyl, mono-C₁-C₆ ordi-C₂-C₁₂) alkyl-aminocarbonyl, mono-C₁-C₆ ordi-C₂-C₁₂)alkylamino-thiocarbonyl, C₁-C₆alkoxy-aminocarbonyl,C₁-C₆alkoxyamino-thiocarbonyl, C₁-C₆alkoxy-carbonyl,C₁-C₆alkoxy-C₁-C₆alkyl-carbonyl, C₁-C₆alkoxy-thiocarbonyl,C₁-C₆alkylthio-carbonyl, C₁-C₆alkylthio-thiocarbonyl,C₁-C₆alkylsulfonyl, C₁-C₆haloalkylsulfonyl, C₃-C₆cycloalkyl-carbonyl,C₂-C₄ alkenyl-carbonyl, C₂-C₄alkynyl-carbonyl,C₂-C₄alkynyl-C₁-C₂alkyl-carbonyl, C₃-C₆cycloalkyl-C₁-C₂alkyl- carbonyl,C₁-C₆alkylthio-C₁-C₆alkyl-carbonyl,C₁-C₆alkylsulfinyl-C₁-C₆alkyl-carbonyl, C₁-C₆alkylsulfonyl-C₁-C₆alkyl-carbonyl,C₁-C₆alkylcarbonyl-C₁-C₆alkyl-carbonyl, C₃-C₆cycloalkylamino-carbonyl,C₂-C₄ alkenylamino-carbonyl, C₁-C₆alkynylamino-carbonyl, —CH₂—R³⁰⁻,—C(O)R³⁰ or —C(S)R³⁰ and each group from C₁-C₆alkyl-carbonyl toC₁-C₆alkynylamino-carbonyl among the definitions of R²⁸ may beoptionally substituted. In one group of compounds R⁸ isC₁-C₆alkyl-carbonyl, C₁-C₆haloalkyl-carbonyl,C₃-C₆cycloalkyl-C₁-C₂alkyl-carbonyl or C₃-C₆cycloalkyl-carbonyl.

R²⁹ is hydrogen, amino, hydroxy, cyano, alkyl, haloalkyl, cycloalkyl,alkenyl, alkynyl, alkylimino, alkoxy, alkylcarbonyl, alkylcarbonylamino,alkoxyalkyl, cyanoalkyl, alkoxycarbonylalkyl, —CH₂—R³⁰, —C(O)R³⁰ or—C(S)R³⁰, and each group from alkyl to alkylcarbonylamino among thedefinitions of R⁹ may be substituted;

preferably R²⁹ is hydrogen, amino, hydroxy, cyano, C₁-C₁₂alkyl,C₁-C₁₂haloalkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₁₂alkylimino, C₁-C₁₂alkoxy, C₁-C₁₂alkyl-carbonyl,C₁-C₁₂alkyl-carbonylamino, C₁-C₁₂alkoxy-C₁-C₁₂alkyl, C₁-C₁₂cyanoalkyl,C₁-C₁₂alkoxycarbonyl-C₁-C₁₂alkyl, —CH₂—R³⁰, —C(O)R³⁰, or —C(S)R³⁰ andeach group from C₁-C₁₂alkyl alkyl to C₁-C₁₂alkoxycarbonyl-C₁-C₁₂alkylamong the definitions of R²⁹ may be optionally substituted; preferablyR²⁹ is hydrogen, amino, hydroxy, cyano, C₁-C₆alkyl, C₁-C₁₂haloalkyl,C₃-C₆ cycloalkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkylimino,C₁-C₆alkoxy, C₁- C₆alkyl-carbonyl, C₁-C₆alkyl-carbonylamino,C₁-C₆alkoxy-C₁-C₆alkyl, C₃-C₆cyanoalkyl, C₁-C₆alkoxycarbonyl-C₁-C₆alkyl,—CH₂—R³⁰, —C(O)R³⁰ or —C(S)R³⁰, and each group from C₁-C₆alkyl toC₁-C₆alkoxycarbonyl-C₁-C₆alkyl, among the definitions of R²⁹ may beoptionally substituted. In one group of compounds R⁹ is hydrogen,C₁-C₆alkoxy or benzyl.

R²⁸ and R²⁹, together with the N atom to which they are bound, may forma 3- to 6-membered heterocyclic ring which may be substituted and mayfurther comprise N, O or S.

R³⁰ is phenyl which may be substituted, a 5- to 6-membered heterocyclicgroup which may be substituted and comprises at least one of N, O and S,optionally substituted C₁-C₁₂alkyl, amino, mono-C₁-C₁₂ ordi(C₂-C₂₄)alkylamino; preferably optionally substituted phenyl, pyridyl,pyrimidinyl, or a group (H1) to (H9), or an optionally substitutedC₁-C₆alkyl, amino, mono-C₁-C₆ or di(C₁-C₁₂)alkylamino group.

Preferably R¹⁰⁰ is C₁-C₁₂ alkyl, phenyl or heteroaryl as defined above,optionally substituted with one to five groups independently selectedfrom cyano, halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, andC₁-C₄haloalkoxy, more preferably C₁-C₆alkyl, most preferably ethyl.

In one group of compounds, group A1 (applicable to all compounds of theinvention bearing a group R¹ and R²):

R¹ is trifluoromethyl.

R² is group A

B¹, B², B³, B⁴ are independently C-Q¹ or nitrogen;

each Q¹ is independently hydrogen, halogen, cyano, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy or C₁-C₈haloalkoxy.

In one group of compounds, group A2, (applicable to all compoundsbearing the group A′) A′ is selected from P1 to P6;

A¹, A², A³, and A⁴ are independently of each other C—H, C—R⁵, ornitrogen;

A^(1′), A^(2′), A^(3′), A^(4′), A^(5′) and A^(6′) are independently ofeach other C—H, C—R⁵ or nitrogen provided that no more than two ofA^(1′), A^(2′), A^(3′), A^(4′), A^(5′) and A^(6′) are nitrogen;

each R⁵ is independently hydrogen, halogen, C₁-C₈alkyl, C₁-C₈haloalkylor C₂-C₈alkenyl;

Q is cyano, halogen, nitro, NH₂, arylsulfonyl or arylsulfonylsubstituted by one to five groups independently selected from C₁-C₄alkyland nitro, heterocyclyl or heterocyclyl substituted by one to five Z¹,—OR¹⁴, —C(═O)N(R⁶)R⁷, —CO(═O)R^(7a), —C(═O)R¹³, or—C(R¹⁵)(R¹⁶)N(R¹⁷)R¹⁸;

k is 0, 1, or 2;

R⁶ is hydrogen, methyl, ethyl, methylcarbonyl or methoxycarbonyl;

R⁷ is hydrogen, C₁-C₈alkyl or C₁-C₈alkyl substituted by one to five R⁸,C₃-C₁₀cycloalkyl or C₃-C₁₀cycloalkyl substituted by one to five R⁹,aryl-C₁-C₆alkylene or aryl-C₁-C₆alkylene wherein the aryl moiety issubstituted by one to five R¹⁰, heterocyclyl-C₁-C₆alkylene orheterocyclyl-C₁-C₆alkylene wherein the heterocyclyl moiety issubstituted by one to five R¹⁰ and wherein each heterocyclyl moietycontains one or more ring members independently selected from O, N, C═O,C═N—OR¹², N—R¹², S, SO, SO₂, S═N—R¹² and SO═N—R¹², aryl or arylsubstituted by one to five R¹⁰, heterocyclyl or heterocyclyl substitutedby one to five R¹⁰ and wherein each heterocyclyl moiety contains one ormore ring members independently selected from O, N, C═O, C═N—OR¹²,N—R¹², S, SO, SO₂, S═N—R¹² and SO═N—R¹², C₁-C₈ alkyl-N(R⁶)—C(═O)—C₁-C₄alkylene, C₁-C₈haloalkyl-N(R⁶)—C(═O)—C₁-C₄alkylene,C₃-C₈cycloalkylaminocarbonyl-C₁-C₄alkylene, C₁-C₆alkyl-O—N═CH—, orC₁-C₆haloalkyl-O—N═CH;

R^(7a) is hydrogen, C₁-C₁₅alkyl or C₁-C₁₅alkyl substituted by one tofive R⁸, C₂-C₁₅alkenyl or C₂-C₁₅alkenyl substituted by one to five R⁸,C₂-C₁₅alkynyl or C₂-C₁₅alkynyl substituted by one to five R⁸,C₃-C₁₀cycloalkyl or C₃-C₁₀cycloalkyl substituted by one to five R⁹,aryl-C₁-C₆alkylene or aryl-C₁-C₆alkylene wherein the aryl moiety issubstituted by one to five R¹⁰, heteroaryl-C₁-C₆alkylene orheteroaryl-C₁-C₆alkylene wherein the heteroaryl moiety is substituted byone to five R¹⁰, or heteroaryl or heteroaryl substituted by one to fiveR¹⁰;

R^(7b) is hydrogen, C₁-C₁₅ alkyl, C₁-C₁₅haloalkyl, C₂-C₁₅ alkenyl,C₂-C₁₅haloalkenyl, C₂-C₁₅ alkynyl, C₂-C₁₅haloalkynyl, C₃-C₁₀cycloalkyl,C₁-C₁₅ alkylcarbonyl or C₁-C₁₅alkoxycarbonyl;

each R⁸ is independently halogen, cyano, nitro, hydroxy, C₁-C₈alkoxy,C₁-C₈haloalkoxy, C₁-C₈alkylcarbonyl, C₁-C₈alkoxycarbonyl, mercapto,C₁-C₈alkylthio, C₁-C₈haloalkylthio, C₁-C₈ alkylsulfinyl,C₁-C₈haloalkylsulfinyl, C₁-C₈alkylsulfonyl;

each R⁹ is independently halogen or C₁-C₈alkyl. Preferably, each R⁹ isindependently chloro, fluoro or methyl;

each R¹⁰ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy;

each R¹¹ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy or C₁-C₈alkoxycarbonyl;

each R¹² is independently hydrogen, cyano, C₁-C₈alkyl, C₁-C₈haloalkyl,C₁-C₈alkylcarbonyl, C₁-C₈haloalkylcarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈haloalkoxycarbonyl, C₁-C₈alkylsulfonyl, C₁-C₈haloalkylsulfonyl,aryl-C₁-C₄alkylene or aryl-C₁-C₄alkylene where the aryl moiety issubstituted by one to three R¹¹, or heteroaryl-C₁-C₄alkylene orheteroaryl-C₁-C₄alkylene where the heteroaryl moiety is substituted byone to three R¹¹;

R¹³ is halogen or imidazole;

each R¹⁴ is independently hydrogen, C₁-C₈alkyl, phenylsulfonyl orphenylsulfonyl substituted by one to five groups independently selectedfrom C₁-C₄alkyl and nitro;

R¹⁵ and R¹⁶ are each independently hydrogen, C₁-C₁₂alkyl,C₁-C₁₂haloalkyl, C₃-C₈cycloalkyl, C₃-C₈halocycloalkyl, C₂-C₁₂alkenyl orC₂-C₁₂haloalkenyl, C₂-C₁₂alkynyl, C₂-C₁₂haloalkynyl cyano,C₁-C₁₂alkoxycarbonyl, C₁-C₁₂haloalkoxycarbonyl,C₁-C₁₂alkoxythiocarbonyl, C₁-C₁₂haloalkoxythiocarbonyl, or R¹⁵ and R¹⁶together with the carbon atom to which they are attached may form a 3 to6-membered carbocyclic ring;

R¹⁷ is hydrogen, NH₂, hydroxyl, C₁-C₁₂alkoxy, C₁-C₁₂haloalkoxy,C₁-C₁₂alkylcarbonylamino, C₁-C₁₂haloalkylcarbonylamino,C₁-C₁₂alkylamino, C₁-C₁₂haloalkylamino, C₁-C₁₂alkyl, C₁-C₁₂haloalkyl,C₃-C₈cycloalkyl, C₃-C₈halocycloalkyl, cyano, C₁-C₁₂alkenyl, C₁-C₁₂haloalkenyl, C₂-C₁₂alkynyl, C₂-C₁₂haloalkynyl, C₁-C₁₂alkylcarbonyl,C₁-C₁₂haloalkylcarbonyl, C₁-C₈alkoxycarbonyl, orC₁-C₈haloalkoxycarbonyl;

R¹⁸ is hydrogen, cyano, carbonyl, thiocarbonyl, C₁-C₁₂alkylcarbonyl,C₁-C₁₂haloalkylcarbonyl, C₁-C₁₂alkylthiocarbonyl,C₁-C₁₂haloalkylthiocarbonyl, C₁-C₁₂alkylaminocarbonyl,C₁-C₁₂alkylaminothiocarbonyl, C₂-C₂₄ (total carbon number)dialkylaminocarbonyl, C₂-C₂₄ (total carbon number)dialkylaminothiocarbonyl, C₁-C₁₂alkoxyaminocarbonyl,C₁-C₁₂alkoxyaminothiocarbonyl, C₁-C₁₂alkoxycarbonyl,C₁-C₁₂haloalkoxycarbonyl, C₁-C₁₂alkoxythiocarbonyl,C₁-C₁₂haloalkoxythiocarbonyl, C₁-C₁₂thioalkoxycarbonyl,C₁-C₁₂thioalkoxythiocarbonyl, C₁-C₁₂alkylsulfonyl,C₁-C₁₂haloalkylsulfonyl, C₃-C₁₂cycloalkylcarbonyl,C₃-C₁₂halocycloalkylcarbonyl, C₂-C₁₂alkenylcarbonyl,C₂-C₁₂haloalkenylcarbonyl, C₂-C₁₂ alkynylcarbonyl,C₂-C₁₂haloalkynylcarbonyl, C₃-C₁₂cycloalkyl-C₁-C₁₂alkylcarbonyl,C₃-C₁₂halocycloalkyl-C₁-C₁₂alkylcarbonyl,C₂-C₁₂alkylsulfenyl-C₁-C₁₂alkylcarbonyl,C₂-C₁₂haloalkylsulfenyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂alkylsulfinyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂haloalkylsulfinyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂alkylsulfonyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂haloalkylsulfonyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂alkylcarbonyl-C₁-C₁₂alkylcarbonyl,C₁-C₁₂haloalkylcarbonyl-C₁-C₁₂alkylcarbonyl,C₃-C₁₂cycloalkylaminocarbonyl, C₂-C₁₂alkenylaminocarbonyl,C₂-C₁₂alkynylaminocarbonyl. More preferably, R¹⁸ is C₁-C₄alkylcarbonylor C₁-C₄alkylcarbonyl substituted by one to five R⁸, C₃-C₆cycloalkylcarbonyl or C₃-C₆cycloalkylcarbonyl wherein the cycloalkyl issubstituted by one to five R⁹; even more Preferably, R¹⁸ isC₁-C₄alkylcarbonyl, C₁-C₄haloalkylcarbonyl, C₃-C₆cycloalkylcarbonyl orC₃-C₆halocycloalkylcarbonyl;

R¹⁷ and R¹⁸ together with the nitrogen atom to which they are bound mayform a 3- to 6-membered heterocyclic ring which may be substituted byone to five R¹¹, or may be substituted with a keto, thioketo ornitroimino group;

R¹⁹ is aryl or aryl substituted by one to five R¹¹, heterocyclyl orheterocyclyl substituted by one to five R¹¹ wherein aryl is phenyl andthe heterocyclyl is preferably pyridyl;

R²⁰ is hydrogen or C₁-C₈alkyl;

each R²¹ and R²² is independently hydrogen, halogen, C₁-C₈alkyl orC₁-C₈haloalkyl;

each Z¹ is independently halogen, cyano, C₁-C₄alkyl, C₁-C₄haloalkyl,C₁-C₄alkoxy, or C₁-C₄haloalkoxy;

R²⁶ is —N(R²⁸)(R²⁹), halogen, hydroxy, C₁-C₈alkoxy, C₁-C₈haloalkoxy,C₁-C₈alkoxycarbonyl, C₁-C₈haloalkoxycarbonyl, or —CO₂H;

R²⁷ is hydrogen, halogen, hydroxy, hydrogen, C₁-C₈alkyl, C₁-C₈alkoxy,C₁-C₈haloalkoxy, more preferably hydrogen, C₁-C₈alkyl, C₁-C₈alkoxy, orC₁-C₈haloalkoxy;

R²⁶ and R²⁷ may together be oxo, optionally substituted oxime,optionally substituted imine and optionally substituted hydrazone;

R²⁸ is hydrogen, cyano, formyl, thioformyl, C₁-C₁₂alkylcarbonyl,C₁-C₁₂haloalkyl-carbonyl, C₁-C₁₂alkyl-thiocarbonyl,C₁-C₁₂haloalkyl-thiocarbonyl, mono- C₁-C₁₂ ordi-C₂-C₂₄alkyl-aminocarbonyl, mono-C₁-C₁₂ ordi-C₂-C₂₄alkylamino-thiocarbonyl, C₁-C₁₂alkoxy-aminocarbonyl,C₁-C₁₂alkoxyamino-thiocarbonyl, C₁-C₁₂alkoxy-carbonyl,C₁-C₁₂alkoxy-C₁-C₁₂alkyl-carbonyl, C₁-C₁₂alkoxy-thiocarbonyl,C₁-C₁₂alkylthio-carbonyl, C₁-C₁₂alkylthio- thiocarbonyl,C₁-C₁₂alkylsulfonyl, C₁-C₁₂haloalkylsulfonyl, C₃-C₈cycloalkyl-carbonyl,C₂-C₆alkenyl-carbonyl, C₂-C₆alkynyl-carbonyl,C₂-C₆alkynyl-C₁-C₁₂alkyl-carbonyl, C₃-C₈cycloalkyl-C₁-C₁₂alkyl-carbonyl,C₁-C₁₂alkylthio-C₁-C₁₂alkyl-carbonyl,C₁-C₁₂alkyl-sulfinyl-C₁-C₁₂alkyl-carbonyl,C₁-C₁₂alkylsulfonyl-C₁-C₁₂alkyl-carbonyl,C₁-C₁₂alkylcarbonyl-C₁-C₁₂alkyl-carbonyl, C₃-C₈cycloalkylamino-carbonyl,C₂-C₆alkenylamino-carbonyl, C₂-C₆alkynylamino-carbonyl, —CH₂—R¹⁰,—C(O)R¹⁰, or —C(S)R¹⁰, and each group from C₁-C₁₂alkyl-carbonyl toC₂-C₆alkynyl-amino-carbonyl, among the definitions of R⁸ may beoptionally substituted;

R²⁹ is hydrogen, amino, hydroxy, cyano, C₁-C₁₂alkyl, C₁-C₁₂haloalkyl,C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₁₂alkylimino,C₁-C₁₂alkoxy, C₁-C₁₂alkyl-carbonyl, C₁-C₁₂alkyl-carbonylamino,C₁-C₁₂alkoxy-C₁-C₁₂alkyl, C₁-C₁₂cyanoalkyl,C₁-C₁₂alkoxycarbonyl-C₁-C₁₂alkyl, —CH₂—R³⁰, —C(O)R³⁰, or —C(S)R³⁰ andeach group from C₁-C₁₂alkyl alkyl to C₁-C₁₂alkoxycarbonyl-C₁-C₁₂alkylamong the definitions of R²⁹ may be optionally substituted;

R²⁸ and R²⁹, together with the N atom to which they are bound, may forma 3- to 6-membered heterocyclic ring which may be substituted and mayfurther comprise N, O or S;

optionally substituted phenyl, pyridyl, pyrimidinyl, or a group (H1) to(H9), or an optionally substituted C₁-C₆alkyl, amino, mono-C₁-C₆ ordi(C₁-C₁₂)alkylamino group;

wherein unless otherwise stated optionally substituents areindependently selected from cyano, halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,C₁-C₄alkoxy, and C₁-C₄haloalkoxy.

In one group of compounds, group A3, (applicable to all compounds of theinvention bearing group A′) A′ is P1 or P2;

A¹, A² and A³ are C—H;

Q is cyano, halogen, nitro, NH₂, C₁-C₈alkoxy, phenylsulfonyl orphenylsulfonyl substituted by one to five groups independently selectedfrom C₁-C₄ alkyl and nitro, —C(═O)N(R⁶)R⁷, —CO(═O)R^(7a), —C(═O)R¹³,—C(R¹⁵)(R¹⁶)N(R¹⁷)R¹⁸, or a heterocycle selected from H1 to H9;

k is 0, 1 or 2, preferably 0;

each R⁵ is independently halogen, C₁-C₈alkyl, C₁-C₈haloalkyl orC₂-C₈alkenyl;

R⁶ is hydrogen;

R⁷ is hydrogen, C₁-C₈alkyl, C₁-C₈haloalkyl, phenyl-C₁-C₆alkylene orphenyl-C₁-C₆alkylene wherein the phenyl moiety is substituted by one tofive R¹⁰, pyridyl-C₁-C₆alkylene or pyridyl-C₁-C₆alkylene wherein thepyridyl moiety is substituted by one to four R¹⁰,thiazolyl-C₁-C₆alkylene or thiazolyl-C₁-C₆alkylene wherein the thiazolylmoiety is substituted by one or two R¹⁰, phenyl or phenyl substituted byone to five R¹⁰, pyridyl or pyridyl substituted by one to four R¹⁰,thiazolyl or thiazolyl substituted by one or two R¹⁰, C₃-C₆cycloalkyl orC₃-C₆cycloalkyl wherein one ring atom is replaced by O or S, C₁-C₄alkylO—N═CH—, C₁-C₄haloalkyl-O—N═CH—, C₁-C₄alkyl-N(R⁶)—C(═O)—CH₂—,C₁-C₄haloalkyl-N(R⁶)—C(═O)—CH₂—, or a group of formula (Y)

L is a single bond or C₁-C₆alkylene, preferably a bond;

Y¹, Y² and Y³ are independently of another O, CR²¹R²², C═O, C═N—OR¹²,N—R¹², S, SO, SO₂, S═N—R¹² or SO═N—R¹², provided that at least one ofY¹, Y² or Y³ is not CR²¹R²², C═O or C═N—OR¹², preferably two of Y¹, Y²and Y³ are CH₂ and the other is S, SO or SO;

R^(7a) is C₁-C₁₅alkyl, C₁-C₁₅haloalkyl, C₂-C₁₅alkenyl,C₂-C₁₅haloalkenyl, pyridyl or benzyl;

each R⁸ is independently halogen, cyano, nitro, hydroxy, C₁-C₈alkoxy,C₁-C₈haloalkoxy, mercapto, C₁-C₈alkylthio, C₁-C₈haloalkylthio;

each R⁹ is independently halogen or C₁-C₈alkyl;

each R¹⁰ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy;

each R¹¹ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy or C₁-C₈alkoxycarbonyl;

each R¹² is independently hydrogen, cyano, C₁-C₈alkyl, C₁-C₈haloalkyl,C₁-C₈alkylcarbonyl, C₁-C₈haloalkylcarbonyl, C₁-C₈alkoxycarbonyl,C₁-C₈haloalkoxycarbonyl, C₁-C₈alkylsulfonyl, C₁-C₈haloalkylsulfonyl,phenyl-C₁-C₄alkylene or phenyl-C₁-C₄alkylene where the phenyl moiety issubstituted by one to three R¹¹, or pyridyl-C₁-C₄alkylene orpyridyl-C₁-C₄alkylene where the pyridyl moiety is substituted by one tothree R¹¹;

R¹³ is halogen or imidazole, preferably chloro, fluoro or bromo;

R¹⁵ and R¹⁶ are each independently hydrogen, halogen, cyano, C₁-C₄alkylor C₁-C₄haloalkyl;

R¹⁷ is hydrogen, C₁-C₅alkyl, C₁-C₅alkoxy, C₁-C₅alkylcarbonyl, orC₁-C₅alkoxycarbonyl;

R¹⁸ is C₁-C₄alkylcarbonyl or C₁-C₄alkylcarbonyl substituted by one tofive R⁸, C₃-C₆ cycloalkylcarbonyl or C₃-C₆cycloalkylcarbonyl wherein thecycloalkyl is substituted by one to five R⁹;

R²⁰ is hydrogen or C₁-C₅alkyl, preferably hydrogen;

each Z¹ is independently hydrogen, halogen, methyl, halomethyl, methoxyor halomethoxy;

R²⁶ is —N(R²⁸)(R²⁹), halogen, hydroxy, C₁-C₅alkoxy, C₁-C₈haloalkoxy,C₁-C₅alkoxycarbonyl, C₁-C₅haloalkoxycarbonyl, or —CO₂H;

R²⁷ is hydrogen, C₁-C₅alkyl, C₁-C₅alkoxy, or C₁-C₈haloalkoxy.

R²⁸ is C₁-C₆alkyl-carbonyl, C₁-C₆haloalkyl-carbonyl,C₃-C₆cycloalkyl-C₁-C₂alkyl-carbonyl or C₃-C₆cycloalkyl-carbonyl;

R²⁹ is hydrogen, C₁-C₆alkoxy or benzyl.

In one group of compounds, group A4, applicable to all compounds of theinvention bearing a group R¹, R² and A′, R¹ and R² are as defined ingroup A1 and A′ is as defined in group A2.

In one group of compounds, group A5, applicable to all compounds of theinvention bearing a group R¹, R² and A′, R¹ and R² are as defined ingroup A1 and A′ is as defined in group A3.

In one group of compounds, group A6, applicable to all compounds of theinvention bearing a group P, P is C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl,N-1,2,4-triazolyl, N-benzotriazolyl, or C₁-C₆alkylsulfinyl.

In one group of compounds, group A7, applicable to all compounds of theinvention bearing a group P, optionally P is not C₁-C₆alkoxy,N-pyrrolyl, N-imidazolyl, N-1,2,4-triazolyl, N-benzotriazolyl, orC₁-C₆alkylsulfinyl.

In one group of compounds, group A8, applicable to all compounds of theinvention bearing a group R², R² is aryl or aryl substituted by one tofive R⁷⁰, or heteroaryl or heteroaryl substituted by one to five R⁷⁰,preferably phenyl or phenyl substituted by one to five R⁷⁰, morepreferably phenyl substituted by one to three R⁷⁰, even more preferablyR² is 3-chloro-5-trifluoromethyl-phenyl-, 3,5-dichloro-phenyl-,3,5-bis-(trifluoromethyl)-phenyl-, 3,5-dichloro-4-fluoro-phenyl-,3,4,5-trichloro-phenyl- or 3-trifluoromethyl-phenyl-, most preferably3,5-dichloro-phenyl; each R⁷⁰ is independently halogen, cyano, nitro,C₁-C₈alkyl, C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl,C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy, C₁-C₈alkoxy-, C₁-C₈haloalkoxy-,mercapto, C₁-C₅alkylthio-, C₁-C₈haloalkylthio-, C₁-C₈alkylsulfinyl-,C₁-C₈haloalkylsulfinyl-, C₁-C₅alkylsulfonyl-, C₁-C₈haloalkylsulfonyl-,C₁-C₅alkylcarbonyl-, C₁-C₅alkoxycarbonyl-, aryl or aryl substituted byone to five R⁷¹, or heterocyclyl or heterocyclyl substituted by one tofive R⁷¹; preferably halogen, cyano, C₁-C₅alkyl, C₁-C₈haloalkyl orC₁-C₈alkoxy-, more preferably bromo, chloro, fluoro, cyano, methyl,trifluoromethyl, methoxy or trifluoromethoxy, preferably bromo, chloro,fluoro or trifluoromethyl, most preferably bromo or chloro; each R⁷¹ isindependently halogen, cyano, nitro, C₁-C₈alkyl, C₁-C₈haloalkyl,C₁-C₈alkoxy-, C₁-C₈haloalkoxy- or C₁-C₈alkoxycarbonyl-, preferablybromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl,methoxy, difluoromethoxy or trifluoromethoxy, more preferably bromo,chloro, fluoro, nitro or methyl, most preferably chloro, fluoro ormethyl.

In one group of compounds, group A9, applicable to all compounds of theinvention bearing a group R², optionally R² is not aryl or arylsubstituted by one to five R⁷⁰, or heteroaryl or heteroaryl substitutedby one to five R⁷⁰, each R⁷⁰ is independently halogen, cyano, nitro,C₁-C₈alkyl, C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy, C₁-C₈alkoxy-, C₁-C₈haloalkoxy-,mercapto, C₁-C₈alkylthio-, C₁-C₈haloalkylthio-, C₁-C₈alkylsulfinyl-,C₁-C₈haloalkylsulfinyl-, C₁-C₈alkylsulfonyl-, C₁-C₈haloalkylsulfonyl-,C₁-C₈alkylcarbonyl-, C₁-C₅alkoxycarbonyl, aryl or aryl substituted byone to five R⁷¹, or heterocyclyl or heterocyclyl substituted by one tofive R⁷¹; each R⁷¹ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy-, C₁-C₈haloalkoxy- or C₁-C₈alkoxycarbonyl-.

In one group of compounds, group A10, applicable to all compounds of theinvention bearing a group R², R² is phenyl substituted by one to threeR⁷; each R⁷ is independently halogen, cyano, C₁-C₈alkyl, C₁-C₈haloalkylor C₁-C₈alkoxy-;

In one group of compounds, group A11, applicable to all compounds of theinvention bearing a group R², optionally R² is not phenyl substituted byone to three R⁷⁰; each R⁷⁰ is independently halogen, cyano, C₁-C₈alkyl,C₁-C₈haloalkyl or C₁-C₈alkoxy-;

In one group of compounds, group A12, applicable to all compounds of theinvention bearing a group R², R² is 3-chloro-5-trifluoromethyl-phenyl-,3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-,3,5-dichloro-4-fluoro-phenyl-, 3,4,5-trichloro-phenyl- or3-trifluoromethyl-phenyl-.

In one group of compounds, group A13, applicable to all compounds of theinvention bearing a group R², optionally R² is not3-chloro-5-trifluoromethyl-phenyl-, 3,5-dichloro-phenyl-,3,5-bis-(trifluoromethyl)-phenyl-, 3,5-dichloro-4-fluoro-phenyl-,3,4,5-trichloro-phenyl- or 3-trifluoromethyl-phenyl-.

In one group of compounds, group A14, applicable to all compounds of theinvention bearing a group R², R² is aryl or aryl substituted by one tofive R⁷⁰, or heteroaryl or heteroaryl substituted by one to five R⁷⁰,preferably phenyl or phenyl substituted by one to five R⁷; each R⁷⁰ isindependently halogen, cyano, nitro, C₁-C₈alkyl, C₁-C₈haloalkyl,C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy,C₁-C₈alkoxy-, C₁-C₈haloalkoxy-, mercapto, C₁-C₈alkylthio-,C₁-C₈haloalkylthio-, C₁-C₈alkylsulfinyl-, C₁-C₈haloalkylsulfinyl-,C₁-C₈alkylsulfonyl-, C₁-C₈haloalkylsulfonyl-, C₁-C₅alkylcarbonyl-,C₁-C₈alkoxycarbonyl-, aryl or aryl substituted by one to five R⁷¹, orheterocyclyl or heterocyclyl substituted by one to five R⁷¹; each R⁷¹ isindependently halogen, cyano, nitro, C₁-C₈alkyl, C₁-C₈haloalkyl,C₁-C₈alkoxy-, C₁-C₈haloalkoxy- or C₁-C₈alkoxycarbonyl-.

In one group of compounds, group A15, applicable to all compounds of theinvention bearing a group R², optionally R² is not aryl or arylsubstituted by one to five R⁷⁰, or heteroaryl or heteroaryl substitutedby one to five R⁷⁰, preferably phenyl or phenyl substituted by one tofive R⁷; each R⁷⁰ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl,C₂-C₈haloalkynyl, hydroxy, C₁-C₈alkoxy-, C₁-C₈haloalkoxy-, mercapto,C₁-C₈alkylthio-, C₁-C₈haloalkylthio-, C₁-C₈alkylsulfinyl-,C₁-C₈haloalkylsulfinyl-, C₁-C₈alkylsulfonyl-, C₁-C₈haloalkylsulfonyl-,C₁-C₈alkylcarbonyl-, C₁-C₈alkoxycarbonyl-, aryl or aryl substituted byone to five R⁷¹, or heterocyclyl or heterocyclyl substituted by one tofive R⁷¹; each R⁷¹ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈halo alkyl, C₁-C₈alkoxy-, C₁-C₈haloalkoxy- or C₁-C₈alkoxycarbonyl-.

In one group of compounds, group A16, applicable to all compounds of theinvention bearing a group A′, A′ may be group C

A^(1a), A^(2a), A^(3a) and A^(4a) are independently of each other C—H,C—R^(5a) or nitrogen;G^(1a) is oxygen or sulfur;R^(1a) is hydrogen, C₁-C₈alkyl, C₁-C₈alkoxy-, C₁-C₈alkylcarbonyl-,C₁-C₈alkoxycarbonyl- or C₁-C₈haloalkoxycarbonyl-;

R^(2a) is a group of formula D

whereLa is a single bond or C₁-C₆alkylene; and

Y^(1a), Y^(2a) and Y^(3a) are independently of another CR^(8a)R^(9a),C═O, C═N—OR^(10a), N—R^(10a), S, SO, SO₂, S═N—R^(10a) or SO═N—R^(10a),provided that at least one of Y^(1a), Y^(2a) or Y^(3a) is notCR^(8a)R^(9a), C═O or CN—OR^(10a), preferably thietan-3-yl-,1-oxo-thietan-3-yl-, 1,1-dioxo-thietan-3-yl- or 3-methyl-thietan-3-yl-,more preferably thietan-3-yl-, 1-oxo-thietan-3-yl-, or1,1-dioxo-thietan-3-yl-;

each R^(5a) is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl,C₂-C₈haloalkynyl, C₃-C₁₀cycloalkyl, C₁-C₈alkoxy-, C₁-C₈haloalkoxy-,C₁-C₈alkylthio-, C₁-C₈haloalkylthio-, C₁-C₈alkylsulfinyl-,C₁-C₈haloalkylsulfinyl-, C₁-C₈alkylsulfonyl- or C₁-C₈haloalkylsulfonyl-,or

two R^(5a) on adjacent carbon atoms together form a —CH═CH—CH═CH—bridge;

R^(6a) is hydrogen, C₁-C₈haloalkyl or C₁-C₈alkyl;

each R^(8a) and R^(9a) is independently hydrogen, halogen, C₁-C₈alkyl orC₁-C₈haloalkyl;

each R^(10a) is independently hydrogen, cyano, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkylcarbonyl-, C₁-C₈haloalkylcarbonyl-,C₁-C₈alkoxycarbonyl-, C₁-C₈haloalkoxycarbonyl-, C₁-C₈alkylsulfonyl-,C₁-C₈haloalkylsulfonyl-, aryl-C₁-C₄alkylene- or aryl-C₁-C₄alkylene wherethe aryl moiety is substituted by one to three R^(12a), orheteroaryl-C₁-C₄alkylene- or heteroaryl-C₁-C₄alkylene- where theheteroaryl moiety is substituted by one to three R^(12a);

each R^(11a) and R^(12a) is independently halogen, cyano, nitro,C₁-C₅alkyl, C₁-C₈haloalkyl, C₁-C₈alkoxy-, C₁-C₈haloalkoxy- orC₁-C₅alkoxycarbonyl-.

In one group of compounds, group A17, applicable to all compounds of theinvention bearing a group A′, optionally A′ is not A′ as defined ingroup A16.

Examples of chiral catalysts include chiral cinchona alkaloidderivatives, chiral thiourea derivatives, chiral urea derivatives,chiral aza-crown ether derivatives, chiral metal complexes, chiralamidine and guanidine derivatives, chiral pyrrolidine and imidazolidinederivatives, chiral scandium III complexes, chiral naphthyl phasetransfer catalysts, chiral galodinium or strontium catalysts, chiralcrown ether derivatives and chiral ligands for alkaline earth metals.

Chiral cinchona alkaloid derivatives are preferred and include alkaloidderivatives of the quaternary ammonium salts, tertiary aminederivatives, urea derivatives, thiourea derivatives and squaramidederivatives.

The term “chiral cinchona alkaloid derivatives” may overlap with theterms “chiral thiourea derivative” and “chiral urea derivative”.Accordingly, the term “Chiral cinchona alkaloid derivatives” may in someembodiments exclude chiral thiourea derivatives and chiral ureaderivatives. However, unless explicitly indicated the term “Chiralcinchona alkaloid derivatives” will include the relevant chiral thioureaderivatives and chiral urea derivatives.

In one embodiment the chiral catalysts are thiourea derivatives andchiral urea derivatives, in particular those that contain in themolecule a basic nitrogen atom in addition to the two nitrogen atoms ofthe urea or thiourea moiety, e.g. a primary, secondary or tertiary amineExamples include chiral cinchona alkaloid thiourea derivatives, chiralcinchona alkaloid urea derivatives, thiourea derivatives ofcyclohexanediamine and urea derivatives of cyclohexanediamine Chiralcinchona alkaloid thiourea derivatives and thiourea derivatives ofcyclohexanediamine are preferred.

For the nitromethane addition the preferred chiral catalysts arecinchona alkaloid derivatives, chiral thiourea derivatives and chiralmetal complexes. These catalysts include those from groups 1, 2, 3, 4,5, 7 and 11 below. Particularly preferred catalysts for are chiralcinchona alkaloid derivatives, particularly cinchona alkaloidderivatives of quaternary ammonium salts, cinchona alkaloid ureaderivatives, cinchona alkaloid thiourea derivatives, and cinchonaalkaloid squaramide derivatives. Even more preferred are cinchonaalkaloid urea derivatives, cinchona alkaloid thiourea derivatives, mostpreferred being cinchona alkaloid thiourea derivatives.

For the cyanide addition the preferred catalysts are cinchona alkaloidderivatives, chiral ruthenium catalysts as well as gadolinium andstrontium catalysts. These catalysts include those from groups 1, 2, 3,4, 7 and 13. Most preferred catalysts are derivatives of cinchonaalkaloid quaternary ammonium salts.

Examples of cinchona alkaloid quaternary ammonium salt derivativesinclude compounds of formula 1 (group 1)

wherein

W¹ is ethyl or vinyl; R³⁰ is hydrogen or C₁-C₄alkoxy; R³¹ is hydroxyl,C₁-C₄alkoxy, C₂-C₄alkenyloxy, optionally substituted aryloxy, optionallysubstituted heteroaryloxy or optionally substituted benzyloxy; R³² isoptionally substituted aryl or optionally substituted heteroaryl; X isan anion.

Preferably W¹ is vinyl.

Preferably R³⁰ is methoxy.

Preferably R³¹ is hydroxyl, C₁-C₄alkoxy, C₂-C₄alkenyloxy, optionallysubstituted heteroaryloxy or benzyloxy, more preferably hydroxyl,optionally substituted pyrimidinyloxy or benzyloxy, most preferablyhydroxyl.

Preferably X is a halogen, more preferably chloride or bromide.Preferably R³² is phenyl or phenyl substituted by one to five R³³,naphthyl or naphthyl substituted by one to five R³³, anthracenyl oranthracenyl substituted by one to five R³³, or heteroaryl or heteroarylsubstituted by one to four R³³; more preferably R³² is phenyl or phenylsubstituted by one to five R³³, naphthyl or naphthyl substituted by oneto five R³³, anthracenyl or anthracenyl substituted by one to five R³³,pyrimidinyl or pyrimidinyl substituted by one to three R³³, or pyridylor pyridyl substituted by one to four R³³; more preferably phenyl orphenyl substituted by one to five R³³, naphthyl or naphthyl substitutedby one to five R³³, anthracenyl or anthracenyl substituted by one tofive R³³, or pyridyl or pyridyl substituted by one to four R³³; morepreferably R³² is phenyl or phenyl substituted by one to five R³³,anthracenyl or anthracenyl substituted by one to five R³³, or pyridyl orpyridyl substituted by one to four R³³; even more preferably R³² isphenyl or phenyl substituted by one to five substituents independentlyselected from halogen, methyl and methoxy, anthracenyl or anthracenylsubstituted by one to five substituents independently selected fromhalogen, methyl and methoxy, pyridyl or pyridyl substituted by one tofour halogen atoms, or group B

or group B substituted by one to four substituents independentlyselected from halogen, methyl and methoxy, even more preferably phenylsubstituted by one to five substituents independently selected fromhalogen methyl and methoxy, anthracenyl or anthracenyl substituted byone to five substituents independently selected from halogen, methyl andmethoxy or pyridyl or pyridyl substituted by one to four halogen atoms,even more preferably phenyl substituted by one to five substituentsindependently selected from halogen methyl and methoxy or anthracenyl.Each R³³ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy, C₁-C₈haloalkoxy, C₃-C₈cycloalkyl, phenyl orphenyl substituted by one to five halogen, and wherein two R³³substituents on adjacent carbon atoms may together form a partiallysaturated 5-7 membered ring containing one or two heteroatomsindependently selected from O, N(R³⁴) and S; and each R³⁴ isindependently hydrogen or C₁-C₄ alkyl. Preferably each R³³ isindependently halogen, cyano, nitro, C₁-C₄alkyl, C₁-C₄haloalkyl,C₁-C₄alkoxy, aryl or C₁-C₄haloalkoxy, and wherein any two R³³substituents on adjacent carbon atoms may together form a partiallysaturated 5 membered ring containing one or two O atoms, more preferablyeach R³³ is independently halogen, methyl, halomethyl, methoxy, phenylor halomethoxy, and wherein any two R³³ substituents on adjacent carbonatoms may together form a partially saturated 5 membered ring containingone or two O atoms, more preferably each R³³ is independently halogen,methyl, phenyl or methoxy, most preferably each R³³ is independentlyfluorine, methyl, phenyl or methoxy.

Examples include

wherein X is an anion, preferably halogen, more preferably chloride orbromide.

Examples of cinchona alkaloid quaternary ammonium salt derivatives aredescribed for example in Arai et al., Tet. Lett. 1999, 4215; S. Colonna,H. Hiemstra, H. Wynberg, J. Chem. Soc. Chem. Commun. 1978, 238; E. J.Corey, F. Y. Zhang, Org. Lett. 2000, 2, 4257; D. Y. Kim, S. C. Huh,Tetrahedron 2001, 57, 8933; M. Hua, H. Cui, L. Wang, J. Nie, J. Ma,Angew. Chem. 2010, 122, 2832; Angew. Chem. Int. Ed. 2010; and T. Ooi, K.Maruoka, Acc. Chem. Res. 2004, 37, 526; Provencher, B. A., Bartelson, K.J., Liu, Y., Foxman, B., Deng, L. Angew. Chem. Int. Ed. 2011, 50, 10565;Liu, Y., Provencher, B. A., Bartelson, K. J., Deng, L. Chem. Sci. 2011,2, 1301

Examples of cinchona alkaloid tertiary amine derivatives includecompounds of formula 2 (group 2)

W² is ethyl or vinyl; R³⁵ is hydrogen or C₁-C₄alkoxy; R³⁶ is hydroxyl,C₁-C₄alkoxy, C₂-C₄alkenyloxy or optionally substituted benzyloxy.

Preferably W² is vinyl.

Preferably R³⁵ is methoxy.

Preferably R³⁶ is hydroxyl, C₁-C₄alkoxy, C₂-C₄alkenyloxy or benzyloxy,most preferably hydroxyl.

Examples include:

as described in A. Latvala, S. Stanchev, A. Linden, M. Hesse, Tet. Asym.1993, 2, 173.

Examples of cinchona alkaloid urea and thiourea derivatives includecompounds of formula 3 (group 3)

Y is S or O, W³ is ethyl or vinyl; R³⁷ is hydrogen or C₁-C₄alkoxy; R³⁸is optionally substituted aryl or optionally substitutedC₃-C₁₀cycloalkyl.

Preferably Y is S.

Preferably W³ is vinyl or ethyl.

Preferably R³⁷ is methoxy.

Preferably R³⁸ is phenyl optionally substituted by one to five R³⁹ orC₅-C₆cycloalkyl optionally substituted by R⁴⁰, more preferably phenyloptionally substituted by one to five R³⁹.

R³⁹ is halogen, cyano, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, preferably C₁-C₄ haloalkyl, more preferablyC₁-C₄haloalkyl.

R⁴⁰ is NH₂, halogen, cyano, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, preferably NH₂.

Examples include

as described in B. Vakulya, S. Varga, A. Csampai, T. Soós, Org. Lett.2005, 7, 1967; B. Vakulya, S. Varga, T. Soós, J. Org. Chem. 2008, 73,3475; P. Li, Y. Wang, X. Liang, J. Ye, Chem. Commun. 2008, 3302; and C.Oliva, A. Silva, F. Paz, J. Calvaleiro, Synlett, 2010, 7, 1123-1127.

Examples of squaramide catalysts include compound of formula 4 (group 4)

wherein W⁴ is ethyl or vinyl; R⁵⁴ is hydrogen or C₁-C₄alkoxy; R⁵⁵ isoptionally substituted aryl.

Preferably W⁴ is vinyl

Preferably R⁵⁴ is methoxy.

Preferably R⁵⁵ is phenyl optionally substituted by one to five R⁵⁶ orC₅-C₆cycloalkyl optionally substituted by R⁴⁰.

R⁵⁶ is halogen, cyano, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, preferably C₁-C₄haloalkyl.

Examples include those wherein in the compound of formula X, R⁵⁴ is H orOMe and R⁵⁵ is 4-CF₃—C₆H₄ or 3,5-(CF₃)₂—C₆H₃ as described in Yang, W.;Du, D. Org. Lett., 2010, 12 (23), 5450-5453.

Examples of thiourea derivatives of cyclohexanediamine or diamines(group 5) include the following

Examples of thiourea derivatives of cyclohexanediamine are described inK. Mei, M. Jin, S. Zhang, P. Li, W. Liu, X. Chen, F. Xue, W. Duan, W.Wang, Org. Lett. 2009, 11, 2864, and B. Vakulya, S. Varga, T. Soós, J.Org. Chem. 2008, 73, 3475.

Examples of thiourea derivatives of diamines are described in He,Tianxiong; Qian, Jing-Ying; Song, Hong-Liang; Wu, Xin-Yan Synlett 2009,19, 3195-319 and Kokotos, C. G.; Kokotos, G., Advanced Synthesis &Catalysis 2009, 351(9), 1355-1362 and Manzano, R.; Andres, J. M.;Alvarez, R.; Muruzabal, M. D.; de Lera, A. R.; Pedrosa, R. Chem. Eur. J.2011, 17, 5931.

Examples of aza-crown ethers (group 6) include compound of formula 5

R⁴¹ is hydrogen, C₁-C₁₀alkyl, C₁-C₁₀hydroxyalkyl C₁-C₅alkoxy-C₁-C₅alkyl,C₁-C₈alkoxycarbonyl, C₁-C₈alkyl optionally substituted aryl,aryl-C₁-C₄alkyl wherein the aryl is optionally substituted,(aryl)₂P(O)C₁-C₄ alkyl wherein each aryl is optionally substituted.

Preferably R⁴¹ is hydrogen, C₁-C₁₀alkyl, C₁-C₁₀hydroxyalkyl,C₁-C₅alkoxy-C₁-C₅alkyl, C₁-C₈alkoxycarbonyl-C₁-C₅alkyl, phenyl,phenyl-C₁-C₄alkyl, (phenyl)₂P(O)C₁-C₄ alkyl.

Examples of aza crown ethers include those wherein R⁴¹ is C₆H₅, CH₂C₆H₅,CH₃— (CH₂)₃, CH₃—(CH₂)₉, CH₂CH₂OH, C₆H₁₁, CH₂CO₂CH₃, hydrogen,CH₂CH₂OCH₃, (CH₂)₄P(O)Ph₂.

Examples of aza-crown ethers are described in P. Bakó, A. Szöllösy, P.Bombicz, L. Töke, Synlett 1997, 291 and T. Bakó, P. Bakó, A. Szöllösy,M. Czugler, G. Keglevich, L. Töke, Tet. Asym. 2002, 203.

Examples of chiral metal complexes (group 7) include the following

as described in G. Sundararajan, N. Prabagaran, Org. Lett. 2001, 3, 389;

as described in Kurono, N.; Nii, N.; Sakaguchi, Y.; Uemura, M.; Ohkuma,T. Angew. Chem. Int. Ed. 2011, 50, DOI: 10.1002/anie.201100939

as described in. Keller, N. Veldman, A. L. Spek, B. L. Feringa,Tetrahedron: Asymmetry 1997, 8, 3403; LaK₃tris((R)-binaphthoxide)) asdescribed in K. Funabashi, Y. Saida, M. Kanai, T. Arai, H. Sasai, M.Shibasaki, Tetrahedron Lett. 1998, 39, 7557; and

(S,S)-(salen)A1

variations thereof include [(S,S)-(salen)Al]₂O, (S,S)-(salen)AlMe,(S,S)-(salen)AlCl and are described in M. S. Taylor, D. N. Zalatan, A.M. Lerchner, E. N. Jacobsen, J. Am. Chem. Soc. 2005, 127, 1313;

in combination with an achiral amine, e.g.2,2,6,6-tetramethylpiperidine, as described in K. Itoh, S. Kanemasa, J.Am. Chem. Soc. 2002, 124, 13394.

Examples of chiral amidines and guanidines (group 8) include compoundsof formula 6

wherein each R⁴² is C(H)Ph₂, or CH₂OR⁴³, wherein R⁴³ is t-BuPh₂Si, H orbenzyl, e.g. as described in A. P. Davis, K. J. Dempsey, Tetrahedron:Asymmetry 1995, 6, 2829;

as described in Zhang, G.; Kumamoto, T.; Heima, T.; Ishikawa, T.Tetrahedron Lett. 2010, 51, 3927.

Where X is a halogen or BF₄ of PF₆, most preferably chloride asdescribed in Ma, T.; Fu, X.; Kee, C. W.; Zong, L.; Pan, Y.; Huang, K.;Tan, C. J. Am. Chem. Soc. 2011, 133, 2828 and

wherein R⁴⁴ and R⁴⁵ are independently C₁-C₄ alkyl, C₁-C₄ alkoxy-C₁-C₄alkyl, TBDMS-C₁-C₄ alkyl or TBDPS-C₁-C₄ alkyl, preferably both R⁴⁴ andR⁴⁵ are either hydroxymethyl, TMDMS-methyl or TBDPS-methyl, and whereinX is an anion, preferably halogen or BF₄—, more preferably chloride orBF₄—, e.g. as described in M. T. Allingham, A. Howard-Jones, P. J.Murphy, D. A. Thomas, P. W. R. Caulkett, Tetrahedron Lett. 2003, 44,8677.

Examples of the pyrrolidine derivatives as chiral catalysts (group 9)include proline, e.g. in combination with trans-2,5-dimethylpiperazineas described in S. Hanessian, V. Pham, Org. Lett. 2000, 2, 2975;

as described in C. E. T. Mitchell, S. E. Brenner and S. V. Ley, Chem.Commun., 2005, 5346 and C. E. T. Mitchell, S. E. Brenner, J.Garcia-Fortanet and S. V. Ley, Org. Biomol. Chem., 2006, 4, 2039;

as described in N. Halland, R. G. Hazell, K. A. Jorgensen, J. Org. Chem.2002, 67, 8331;

as described in C. Oliva, A. Silva, F. Paz, J. Calvaleiro, Synlett,2010, 7, 1123-1127; and

as described in Xu, D.; Shi, S.; Wang, Y. European Journal of OrganicChemistry 2009, (28), 4848-4853.

Examples of chiral imidazoline catalysts (group 10) include

as described in N. Halland, R. G. Hazell, K. A. Jorgensen, J. Org. Chem.2002, 67, 8331; and

as described in A. Prieto, N. Halland, K. A. Jøorgensen, Org. Lett.2005, 7, 3897.

Examples of chiral N,N′-dioxide-scandium III complexes (group 11)include ligand-Sc(OTf)₃ complexes wherein the ligand is a compound offormula 7 or 8

wherein R⁴⁶ and R⁴⁷ are phenyl optionally substituted by one to fivehalogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxyand wherein n is 1 or 2;Examples include those wherein n is 1 and R⁴⁶ is 2,6-iPr₂C₆H₃; n is 1and R⁴⁶ is C₆H₅; n is 1 and R⁴⁶ is 2-MeC₆H₄; n is 2 and R⁴⁶ is2,6-iPr₂C₆H₃; R⁴⁷ is 2,6-iPr₂-C₆H₃; as described in L. Wang, Q. Zhang,X. Zhou, X. Liu, L. Lin, B. Qin, X. Feng, Chemistry-A European Journal,2010, 16, (26), 7696-7699,

Chiral binaphthyl phase transfer catalysts (group 12) include compoundsof formula 11, 12, 13 and 14

wherein R⁴⁸, R²⁹, R⁵⁰ and R⁵² are each independently phenyl or naphthyloptionally substituted by one to five halogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy; each R⁵¹ is C₁-C₅ alkyl orC₁-C₈haloalkyl, R⁵³ is a bond or C₁-C₈ alkylene and X is an anion, e.g.a halogen, preferably chlorine or bromine Examples include those whereineach R⁴⁸ is 3,5-(CF₃)₂(C₆H₃); each R⁴⁸ is 3,4,5-F₃C₆H₂; each R⁴⁹ is3,5-(CF₃)₂(C₆H₃); each R⁴⁹ is 3,4,5-F₃C₆H₂; each R⁵⁰ is3,5-(CF₃)₂(C₆H₃); each R⁵⁰ is 3,4,5-F₃C₆H₂; each R⁵¹ is n-butyl; eachR⁵² is H and R⁵³ is a bond; each R⁵² is H and R⁵³ is ethylene; each R⁵²is H and R⁵³ is propylene; each R⁵² is phenyl and R⁵³ is a bond; eachR⁵² is phenyl and R⁵³ is ethylene; each R⁵² is phenyl and R⁵³ ispropylene; each R⁵² is 3,4,5-F₃C₆H₂ and R⁵³ is a bond; each R⁵² is3,4,5-F₃C₆H₂ and R⁵³ is ethylene; each R⁵² is 3,4,5-F₃C₆H₂ and R⁵³ ispropylene; each R⁵² is, 5-(CF₃)₂C₆H₂ and R⁵³ is a bond; each R⁵² is,5-(CF₃)₂C₆H₂ and R⁵³ is ethylene; each R⁵² is 3,5-(CF₃)₂C₆H₂ and R⁵³ ispropylene; each R⁴⁸ is 2-naphthyl as described in M. Hua, H. Cui, L.Wang, J. Nie, J. Ma, Angew. Chem. 2010, 122, 2832 and T. Ooi, K.Maruoka, Acc. Chem. Res. 2004, 37, 526.

Examples of ligands for galodinium or strontium catalysis (group 13)include compounds of formula 15 and 16

wherein R⁵⁷ is CN or F, R⁵⁸ is H or F; each R⁵⁹ is phenyl or p-tolyl;R⁶⁰ is OH, OMe or Oi-Bu as described in Tanaka, Y.; Kanai, M.;Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 6072; Tanaka, Y.; Kanai, M.;Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 8862.

Examples of crown ether phase transfer catalysis (group 14) includecompounds of formula XXI

wherein each R⁶¹ is is H or benzyl as described in Dehmlow, D. E.;Sauerbier, C. Liebigs Ann. Chem. 1989, 181-185.

Examples of ligands for alkaline earth metal catalysis (group 15)include

as described in Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc.2007, 129, 5364; Tsubogo, T.; Saibo, S.; Seki, K.; Yamashita, Y.;Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321; Kobayashi, S.;Tsubogo, T.; Saito, S.; Yamashita, Y. Org. Lett. 2008, 10, 807

It will be clear to the person skilled in the art that in order toprepare the compounds of the invention with the indicatedstereochemistry, the stereochemistry of the compound of formula II mustbe matched with the corresponding stereochemistry of the catalyst. It isunderstood that the stereochemistry of the catalysts depicted above isappropriate for a compound of formula IA:

The following schemes describe the processes of the invention in moredetail. In the schemes below the stereochemistry at * corresponds to thestereochemistry in the claims. The substituent definitions are asdefined herein.

1) Enantioenriched compounds of formula (II) can be prepared by reactinga compound of formula (I) with a suitable cyanide source in the presenceof a chiral catalyst. Suitable cyanide sources include, but are notlimited to alkali metal cyanides, trimethylsilyl andtert-butyldimethylsilyl cyanides, hydrogen cyanide, CNCO₂Et and acetonecyanohydrin. Depending from the catalyst used, suitable solvents includedioxane, tetrahydrofuran, dichloromethane, t-butylmethyl ether,1,2-dichloroethane, dimethoxyethane, xylenes and toluene. In certaincases additives such as cesium fluoride, cesium chloride, lithiumphenolate or 2,6-dimethylphenol are often required. In most cases it isadvantageous to conduct the reaction in a suitable solvent at dilutionbetween 0.1 M to 1 M, preferably 0.3 M to 0.5 M. The reactiontemperature could be from −40° C. to 100° C., preferably between −20° C.and 50° C. The reaction time is usually between 1 hour and 96 hours,preferably between 6 hours and 24 hours. The amount of catalyst isusually between 0.02 and 0.2 molar equivalents, preferably between 0.05and 0.1 molar equivalents. Certain catalysts require a presence of aLewis acid, such as galodinium trifluoromethansulfonate or strontiumtrifluoromethanesulfonate. If chiral phase transfer catalysts of group Iare used the addition of small amounts of water (between one and fourmolar equivalents) is often beneficial. Conducting the reaction in abiphasic system (water/suitable organic solvent) is, however, usuallydetrimental to chemical reactivity. Suitable conditions for thisasymmetric reaction are disclosed in the literature: (a) Sammis, G. M.;Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442. (b) Sammis, G. M.;Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928. (c) Mazet,C.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2008, 47, 1762. (d)Madhavana, N.; Weck, M. AdV. Synth. Catal. 2008, 350, 419. (e) Mita, T.;Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514.(f) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.;Kanaia, M.; Shibasaki, M. Tetrahedron 2007, 63, 5820. (g) Tanaka, Y.;Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 6072. (h)Bernardi, L.; Fini, F.; Fochi, M.; Ricci, A. Synlett 2008, 1857. (i) JunWang, Wei Li, Yanling Liu, Yangyang Chu, Lili Lin, Xiaohua Liu, andXiaoming Feng Organic Letters (2010), 12, (6), 1280-1283. (j) anaka,Yuta; Kanai, Motomu; Shibasaki, Masakatsu, Journal of the AmericanChemical Society 2010, 132, (26), 8862-8863. (k) Brian A. Provencher,Keith J. Bartelson, Yan Liu, Bruce M. Foxman, Li Deng, Angewandte ChemieInternational Edition.

2) Enantioenriched compounds of formula (V) can be prepared bycyclization of enantioenriched compounds of formula (IV) wherein P ishydroxyl, C₁-C₆alkoxy, N-pyrrolyl, N-azolyl, N-imidazolyl,N-1,2-4-triazolyl, N-benzotriazolyl, C₁-C₆alkylsulfinyl under standardacidic or basic conditions.

3) Enantioenriched compounds of formula (IV) wherein P is e.g. hydroxyl,C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl,N-benzotriazolyl, C₁-C₆alkylsulfinyl can be prepared by selectivereduction of enantioenriched compounds of formula (II) wherein P is e.g.hydroxyl, C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl,N-benzotriazolyl, C₁-C₆alkylsulfinyl. Suitable reducing agents includeiron and zinc in the presence of a strong acid, Raney nickel under theatmosphere of hydrogen, a mixture of titanium (IV) chloride with zinc ortitanium (III) chloride and a mixture of cobalt (II) or nickel (II)chloride with sodium borohydride. A reduction with Raney nickel isperformed in a suitable alcoholic solvents, such as methanol or ethanolat dilution between 0.1 M to 1 M and in most cases it is advantageous toconduct the reaction between 0.3 M to 0.5 M, at temperatures from 20° C.to 60° C. Hydrogen pressure used is from 1 bar to 20 bars and the amountof catalyst used is between 5 and weight percent. The reaction time isusually between 10 min and 6 hours, preferably between 30 min and 2hours. The extent of reduction could potentially be controlled byvarying temperature and pressure of hydrogen. A reduction with zinc andacid is carried out in suitable polar solvents, such asdimethylformamide, which are miscible with water. The pH of a solutionis kept at 1-2 and the amount of zinc powder used is between 2 and 10molar equivalents, preferably between 2 and 4 molar equivalents. Thereaction time is usually between 30 min and 4 hours, preferably between30 min and 1 hour. The reduction with cobalt (II) chloride and sodiumborohydride is carried out in a suitable alcoholic solvent and theamount of sodium borohydride used is between 2 and 10 molar equivalents,preferably between 2 and 4 molar equivalents, amount of cobalt (II)chloride hexahydrate used is between 1 and 10 molar equivalents. Thereaction time is usually between 30 min and 6 hours, preferably between30 min and 2 hours.

4) Alternatively enantioenriched compounds of formula (V) can bedirectly obtained by a reductive cyclization of enantioenriched compoundof formula (II) under the conditions described above.

5) Enantioenriched Compounds of formula (VI) can be obtained by acyclization of enantioenriched compound of formula (V) wherein P is e.g.C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl,N-benzotriazolyl, C₁-C₆alkylsulfinyl under basic conditions such asthose described in Tetrahedron, 39(19), 3055-7; 1983.

6) Enantioenriched Compounds of formula (V) can be obtained by aselective hydrolysis of the nitrile function in Enantioenrichedcompounds of formula (II) by acidic or basic hydrolysis.

7) Enantioenriched compounds of formula (VI) can be obtained by acyclization of enantioenriched compounds of formula (VII) by adehydrating reaction such as those described in Chemistry—A EuropeanJournal, 9(14), 3270-3281; 2003.

8) Enantioenriched Compounds of formula (VII) can be obtained bycomplete hydrolysis of enantioenriched compound of formula (II) underbasic aqueous conditions.

9) Enantioenriched Compounds of formula (IX) can be obtained by treatingan enantioenriched compound of formula (II) with an activating agentunder the conditions described in J. Org. Chem. 2008, 73, 312-315.Suitable activating agents include sulfonyl molecules e.g. SOCl₂ andHCl, trichlorophosphate, triphenylphosphine and diethylazodicarboxylate,1H-imidazole and bromine and triphenylphosphine, phosphoric acid orcatalysts such as dihydridotetrakis(triphenylphosphine)ruthenium(II).

10) Enantioenriched Compounds of formula (VIII) can be obtained bycomplete reduction of enantioenriched compounds of formula (II) whereinP is e.g. C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl,N-benzotriazolyl or C₁-C₆alkylsulfinyl for example with a metal hydridesuch as lithium aluminum hydride (LiAlH₄). For instance according to amethod developed in the literature in Journal of Medicinal Chemistry,51(22), 7144-7153; 2008. Alternatively, suitable conditions involve thetreatment of Enantioenriched compounds of formula (II) under anatmosphere of hydrogen gas in the presence of a metal catalyst, such asthose described in the literature in Bioorganic Chemistry, 36(5),241-251; 2008.

10) Enantioenriched Compounds of formula (XII) can be obtained byreacting a enantioenriched compound of formula (X) and anenantioenriched compound of formula (II) in the presence of a suitabledehydrating agent such as thionyl chloride (SOCl₂). For instanceaccording to a method described in Asian Journal of Chemistry, 19(6),4939-4941; 2007.

11) Enantioenriched Compounds of formula (X) can be obtained byhydrolysis of a enantioenriched compound of formula (II) wherein P ise.g. C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl,N-benzotriazolyl or C₁-C₆alkylsulfinyl in the presence of aqueousmineral acid, such as aqueous sulphuric acid between 1% and 100%weight/weight, or hydrochloric acid between 1% and 100% weight/weightbetween 0.1 M to 5 M. In most cases it is advantageous to conduct thereaction preferably 0.3 M to 0.5 M, at temperatures from 20° C. to 120°C.

12) Enantioenriched Compounds of formula (XVI) can be obtained bytreating a enantioenriched compound of formula (XV) with a suitableactivating agent under the conditions described in the literature, suchas in J. Org. Chem. 2008, 73, 312-315. Suitable activating agentsinclude sulfonyl molecules e.g. SOCl₂, mesylate, tosylate, triflate etc

13) Enantioenriched compounds of formula (XV) can be obtained byreducing an enantioenriched compound of formula (XIV) wherein P is e.g.C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl,N-benzotriazolyl or C₁-C₆alkylsulfinyl with a suitable metal hydridesuch as Lithium aluminum hydride, for instance according to a methoddescribed in the literature in Journal of Medicinal Chemistry, 49(1),399-406; 2006.

14) Enantioenriched Compounds of formula (XIV) can be obtained byreacting a enantioenriched compound of formula (IV) wherein P is e.g.C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl,N-benzotriazolyl or C₁-C₆alkylsulfinyl and a compound of formula (XIII)in the presence of a metal catalyst and a base. Suitable conditions canbe found in the literature in Organic Letters, 11(6), 1449-1452; 2009and in Journal of the American Chemical Society, 132(1), 413-426; 2010.

15) Enantioenriched compounds of formula (XVII) can be obtained bycyclising an enantioenriched compound of formula (XIV) wherein P is e.g.C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl,N-benzotriazolyl or C₁-C₆alkylsulfinyl under neutral conditions, such asthose described in the literature in Bioorganic & Medicinal ChemistryLetters, 19(16), 4733-4739; 2009, or under basic conditions such asthose described in Synlett, (4), 591-594; 2006.

16) Enantioenriched compounds of formula (XVIII) can be obtained bycarrying out a Baeyer-Villiger reactions (M. B. Smith, J. March: March'sadvanced organic chemistry. Wiley, New York 2001.) on compounds (IIa)wherein P is e.g. an optionally substituted aryl or an optionallysubstituted heteroaryl or optionally substituted alkyl. Suitablereagents for the reaction include, but are not limited to m-chloroperoxybenzoic acid and trifluoro peroxyacetic acid. The reaction can beconducted neat or in a suitable solvent such as dichloromethane,chloroform, 1,2-dichloroethane, acetic acid, acetonitrile, methanol,trifluoroacetic acid, 1,4-dioxane, benzene, tert-butyl alcohol. Thereaction temperature could be from −50° C. to 150° C., preferablybetween −20° C. and 100° C. The reaction time is usually between 1 hourand 96 hours, preferably between 1 hour and 24 hours.

17) Enantioenriched compounds of formula (III) could be obtained byreductive cyclization of compounds of formula (XVIII) wherein P is asdefined for compounds of formula (Ha). Suitable reducing agents includeiron a late transition metal selected from Pd, Pt, Ni and Co and asource of hydride such as hydrogen gas, a borohydride salt or borane. Areduction with Raney nickel is performed in suitable alcoholic solvents,such as methanol or ethanol, at temperatures from 20° C. to 60° C.Hydrogen pressure used is from 1bar to 20 bar and the amount of catalystused is between 5 and 20 weight percent. The reaction time is usuallybetween 10 min and 6 hours, preferably between 30 min and 2 hours.

Alternatively, the reductive cyclization can be carried out in thepresence of a borohydride salt, such as sodium borohydride, in thepresence of a cobalt salt, such as cobalt(II) dichloride, in a suitablealcoholic solvent, such as methanol or ethanol, according to theconditions described in the literature Bioorganic & Medicinal ChemistryLetters, 20(2), 704-708; 2010

18) Alternatively the reductive cyclization can be carried out byreacting compounds of formula (XVIII) with borane complexed with asuitable acceptor such as dimethylsulfide or tetrahydrofuran. Suitablesolvents induce tetrahydrofuran and 1,4-dioxane and the reactiontemperature can range between 25 C and 100 C. Appropriate conditions aredescribed in the literature Journal of the American Chemical Society(1988), 110(6), 1679-90.

19) Enantioenriched Compounds of formula (VI) can be obtained bycarrying out a Baeyer-Villiger oxidation reaction on enantioenrichedcompounds of formula (IIc) wherein P is e.g. an optionally substitutedaryl or an optionally substituted heteroaryl. Suitable reagents for thereaction include, but are not limited to m-chloro peroxybenzoic acid,trifluoro peroxyacetic acid and peroxy sulfuric acid. Particularlypreferred reagent is peroxysulfuric acid. Between 1 and 100 equivalentsof the reagent is typically used (e.g. at least 1 equivalent, e.g. up to100 equivalents).

Alternatively, a suitable reagent is peroxide in the presence of acid,preferably a strong acid. Peroxides include, but are not limited tohydrogen peroxide, sodium peroxide, sodium perborate, sodiumpercarbonate, sodium persulfate, potassium persulfate. Particularlypreferred is hydrogen peroxide. The concentration of hydrogen peroxidecan be between 5% and 90%, preferably between 20-40% (e.g. at least 5%,at least 20%, e.g. up to 90%, up to 40%). (% refers to v/v.). Between 1and 100 molar equivalents of the reagent is typically used (e.g. atleast 1 molar equivalent, e.g. up to 100 molar equivalents).

Strong acids are e.g. any acid with pKa lower then acetic acid. Strongacids include, but are not limited to trifluoroacetic acid, nitrobenzoicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, sulfuric acid, Nafion-H. Particularly preferred is sulphuric acid.The concentration of acid, which is preferably sulphuric acid, can bebetween 10% and 99%, preferably between 50-97% (e.g. at least 10%, atleast 50%, e.g. up to 99%, up to 97%) (% refers to v/v.) Between 1 and100 molar equivalents of the reagent is typically used (e.g. at least 1molar equivalent, e.g. up to 100 molar equivalents).

The reaction can be conducted neat or in a suitable solvent. Suitablereagents for the reaction include, but are not limited todichloromethane, dichloroethane, chloroform, carbon tetrachloride,acetic acid. The reaction temperature could be from −50° C. to 150° C.,preferably between −20° C. and 100° C. (e.g. at least −50° C., at least−20° C., e.g. up to 150° C., up to 100° C.). The reaction time isusually between 1 hour and 96 hours, preferably between 1 hour and 24hours (e.g. at least 1 hour, e.g. up to 96 hours, up to 24 hours).

20) Enantioenriched Compounds of formula (VI) can be obtained byhydrolysis of the nitrile function in Enantioenriched compounds offormula (XIX) by acidic or basic hydrolysis followed by a dehydrationreaction.

21) Enantioenriched Compounds of formula (XIX) can be obtained byhydrolysis of Enantioenriched compound of formula (II) under basicaqueous conditions.

22) Enantioenriched Compounds of formula (III) can be prepared bycyclization of a enantioenriched compound of formula (IV) under basic,acidic or neutral conditions.

23) Enantioenriched Compounds of formula (IV) can be prepared byreducing a enantioenriched compound of formula (XX). Suitable reducingagents include iron and zinc in the presence of a strong acid, a mixtureof titanium (IV) chloride with zinc or titanium (III) chloride, or alate transition metal selected from Pd, Pt, Ni and Co and a source ofhydride such as hydrogen gas, a silane, formic acid, a formate salt, ora borohydride salt. A reduction with Raney nickel is performed insuitable alcoholic solvents, such as methanol or ethanol, attemperatures from 20° C. to 60° C. Hydrogen pressure used is from 1barto 20 bar and the amount of catalyst used is between 5 and 20 weightpercent. The reaction time is usually between 10 min and 6 hours,preferably between 30 min and 2 hours. The extent of reduction couldpotentially be controlled by varying temperature and pressure ofhydrogen. A reduction with zinc and acid is carried out in suitablepolar solvents, such as dimethylformamide, which are miscible withwater. The pH of a solution is kept at 1-2 and the amount of zinc powderused is between 2 and 10 molar equivalents, preferably between 2 and 4molar equivalents. The reaction time is usually between 30 min and 4hours, preferably between 30 min and 2 hours.

24) Alternatively, the reduction can be carried out in the presence of asilane, such as triethylsilane, in the presence of a source ofpalladium, such as palladium supported on charcoal, in a suitablealcoholic solvent, such as methanol or ethanol, according to theconditions described in the literature in Journal of Organic Chemistry,72(17), 6599-6601; 2007.

25) Alternatively, the reduction can be carried out in the presence offormic acid or a formate salt, such as ammonium formate, in the presenceof a source of palladium, such as palladium supported on charcoal, in asuitable alcoholic solvent, such as methanol or ethanol, according tothe conditions described in the literature in Synthesis (1986), (2),133-5 and in Organic Letters, 3, 3153-3155; (2001).

26) Alternatively, the reduction can be carried out in the presence of aborohydride salt, such as sodium borohydride, in the presence of anickel salt, such as nickel(II) dichloride hexahydrate, in a suitablealcoholic solvent, such as methanol or ethanol, according to theconditions described in the literature in Organic Letters, 3, 1825-1827;(2001).

27) Alternatively, the reduction can be carried out in the presence of aborohydride salt, such as sodium borohydride, in the presence of acobalt salt, such as cobalt(II) dichloride, in a suitable alcoholicsolvent, such as methanol or ethanol, according to the conditionsdescribed in the literature in Journal of Organic Chemistry, 62(24),8565-8568; 1997.

28) Alternatively enantioenriched compounds of formula (III) can beprepared by reducing and cyclizing enantioenriched compounds of formula(XX) under the reduction conditions described above.

29) Enantioenriched compounds of formula (XX) can be prepared byreacting a compound of formula (I) with nitromethane in an asymmetricfashion, in the presence of a chiral catalyst. Reaction with some chiralcatalysts, notably bifunctional thiourea or urea catalysts, do notrequire any additives. The amount of catalyst is usually between 0.02and 0.2 molar equivalents, preferably between 0.05 and 0.1 molarequivalents. In some instances an additional proton source such as4-nitrophenol or t-butanol is needed or useful. Such methods have beendescribed in the literature: (a) Benedek Vakulya, Szilárd Varga andTibor Soós, Journal of Organic Chemistry (2008), 73, (9), 3475-3480. (b)Tetrahedron Letters (2008), 49, (35), 5220-5223. (c) Roberto Ballini,Giovanna Bosica, Dennis Fiorini, Alessandro Palmieri, and MarinoPetrini, Chem Rev 2005, 105, 933.

In most other cases, however, it is necessary or useful to add a base tothe reaction media. Suitable bases include amines, such astriethylamine, 2,5-dimethylpiperazine, tetramethylpiperidine,4-dimethylamino pyridine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, metalalkoxides, such as sodium t-butoxide, metal carbonates, such aspotassium carbonate or metal fluorides, such as cesium fluoride orcesium chloride and tetrabutylammonium fluoride. In most cases it isadvantageous to conduct the reaction using nitromethane as a solvent atdilution between 0.1 M to 1 M, preferably 0.3 M to 0.5 M. Alternativelysuitable organic solvents could be used, for example toluene,1,2-dichloroethane, dichloromethane, tetrahydrofuran, methanol or ethylacetate at a temperature from 0° C. to 100° C., preferably between 40and 100° C., and at dilution of e.g. between 0.1 M to 1 M. The reactiontime is usually between 12 and 96 hours, preferably between 24 and 72hours. If a solvent other than nitromethane is used, the amount ofnitromethane added is between 1.5 and 20 molar equivalents, preferablybetween 1.5 and 5 molar equivalents.

30) Enantioenriched compounds of formula (IV) can be prepared byreacting a compound of formula (XXI) with an acetophenone of formula(XXII) in the presence of a chiral catalyst. Compounds of formula (XXII)are known in the literature or can be prepared using methods known to aperson skilled in the art (see for example Journal of the AmericanChemical Society (2008), 130(42), 13862-13863) and compounds of formula(XXI) are known in the literature or can be prepared using methods knownto a person skilled in the art (see for example WO2009/080250). In mostcases it is advantageous to conduct the reaction using suitable organicsolvents, for example toluene, 1,2-dichloroethane, dichloromethane,tetrahydrofuran, methanol or ethyl acetate. The temperature is usuallybetween 0° C. and 100° C., preferably between 40 and 100° C. Where asolvent is used the reactants are usually at a dilution of e.g. between0.1 M to 1 M. The reaction time is usually between 1 and 96 hours,preferably between 1 and 24 hours. The amount of catalyst is usuallybetween 0.02 and 0.2 molar equivalents, preferably between 0.05 and 0.1molar equivalents. Reaction with some chiral catalysts, notablybifunctional thiourea or urea catalysts, do not require any additives.In some cases, however, it is necessary or useful to add an acid to thereaction media. Suitable acids are benzoic acids. In some instances anadditional proton source such as 4-nitrophenol, phenols, naphthalenol ort-butanol is needed or useful.

31) Enantioenriched compounds of formula (III) can be prepared byreacting compounds of formula (XXV) with an aqueous base followed byacidification. Suitable bases include but are not limited to alkalimetal hydroxides. The reaction temperature could be between 25 C and 100C, preferably between 40 C and 80 C. Between 1 and 5 equivalents ofalkali metal hydroxide are used. Suitable solvents include, but are notlimited to alcohols (such as ethanol), water and tetrahydrofuran.Suitable acids include sulphuric acid, hydrochloric acid, phosphoricacid and p-toluene sulfonic acid. In some cases heating in a nonpolarsolvent such as toluene is sufficient for decarboxylation.

32) Enantioenriched compounds of formula (XXV) can be prepared by areductive cyclization of compounds of formula (XXIV). Suitable reducingagents include iron and zinc in the presence of a strong acid, a mixtureof titanium (IV) chloride with zinc or titanium (III) chloride, or alate transition metal selected from Pd, Pt, Ni and Co and a source ofhydride such as hydrogen gas, a silane, formic acid, a formate salt, ora borohydride salt. A reduction with Raney nickel is performed insuitable alcoholic solvents, such as methanol or ethanol, attemperatures from 20° C. to 60° C. Hydrogen pressure used is from 1barto 20 bar and the amount of catalyst used is between 5 and 20 weightpercent. The reaction time is usually between 10 min and 6 hours,preferably between 30 min and 2 hours. The extent of reduction couldpotentially be controlled by varying temperature and pressure ofhydrogen. A reduction with zinc and acid is carried out in suitablepolar solvents, such as dimethylformamide, which are miscible withwater. The pH of a solution is kept at 1-2 and the amount of zinc powderused is between 2 and 10 molar equivalents, preferably between 2 and 4molar equivalents. The reaction time is usually between 30 min and 4hours, preferably between 30 min and 2 hours. Suitable conditions forsimilar reductive cyclizations have been describe in the literature, forexample: (a) Okino, Tomotaka; Hoashi, Yasutaka; Furukawa, Tomihiro; Xu,Xuenong; Takemoto, Yoshiji. J. Am. Chem. 1 Soc. (2005), 127(1), 119-125;(b) Ji, Jianguo; Barnes, David M.; Zhang, Ji; King, Steven A.;Wittenberger, Steven J.; Morton, Howard E. J. Am. Chem. Soc. (1999),121(43), 10215-10216

33) Enantioenriched compounds of formula XXIV can be prepared can beprepared by reacting compounds of formula XXI with compounds of formulaXXII in the presence of a chiral catalyst. Depending from the catalystused, suitable solvents include dioxane, tetrahydrofuran,dichloromethane, acetonitrile, t-butylmethyl ether, 1,2-dichloromethane,xylenes and toluene. In most cases it is advantageous to conduct thereaction in a suitable solvent at dilution between 0.1 M to 1 M,preferably 0.3 M to 0.5 M. The reaction temperature could be from −40°C. to 100° C., preferably between −20° C. and 50° C. The reaction timeis usually between 1 hour and 96 hours, preferably between 6 hours and24 hours. The amount of catalyst is usually between 0.02 and 0.2 molarequivalents, preferably between 0.05 and 0.1 molar equivalents.

34) Suitable catalysts and conditions for this asymmetric step are welldescribed in the literature. Representative examples include: (a) Ji,Jianguo; Barnes, David M.; Zhang, Ji; King, Steven A.; Wittenberger,Steven J.; Morton, Howard E. Journal of the American Chemical Society(1999), 121(43), 10215-10216. (b) Cooey, S. H.; Conno, S. J. Angew.Chem. Int. Ed. 2005, 6367. (c) Ye, J.; Dixon, J.; Hynes, P. Chem. Comm2005, 448

35) Enantioenriched compounds of formula (XVI) can be prepared byreduction of Enantioenriched compounds of formula (XVII) with a metalhydride, for instance according to a method developed in the literature:Journal of Pharmaceutical Sciences (1978), 67(7), 953-6.

36) Enantioenriched Compounds of formula (XVII) can be prepared byreaction of Enantioenriched compound of formula (III) with a compound offormula (Va) wherein X^(B) is a leaving group, for example a halogen,such as bromo, as described above).

37) Enantioenriched Compounds of formula (XVI) can be prepared byreduction of enantioenriched compounds of formula (XII) with a metalhydride, for instance according to a method developed in the literature(ARKIVOC, 2003, 5, And U.S. Pat. No. 4,524,206).

Suitable reagents for the reaction include, but are not limited to . . .metal hydride

The reaction can be conducted neat or in a suitable solvent The reactiontemperature could be from −50° C. to 150° C., preferably between −20° C.and 100° C. The reaction time is usually between 1 hour and 96 hours,preferably between 1 hour and 24 hours. The reduction of suchsuccinimides are known to proceed through one or several intermediatesof formula (XXVI), (XXVII), and (XXVIII), which may be optionallyisolated.

38) Enantioenriched compounds of formula (XI), can be prepared byreaction of enantioenriched compound of formula (XIII) wherein X^(B) isa leaving group, for example a halogen, such as bromo, with a compoundof formula (III) in the absence or the presence of a catalyst, such aspalladium(II) acetate or bis(triphenylphosphine)palladium(II)dichloride, optionally in the presence of a ligand, such astriphenylphosphine, and a base, such as sodium carbonate, pyridine,triethylamine, 4-(dimethylamino)-pyridine (“DMAP”) ordiisopropylethylamine (Hunig's base), in a solvent, such as water,N,N-dimethylformamide or tetrahydrofuran. The reaction is carried out ata temperature of from 50° C. to 200° C., preferably from 100° C. to 150°C. The reaction is carried out at a pressure of from 50 to 200 bar,preferably from 100 to 150 bar.

39) Enantioenriched Compounds of formula (VIII) can be obtained byreduction of Enantioenriched compound of formula (XX) wherein P is e.g.C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl,N-benzotriazolyl or C₁-C₆alkylsulfinyl using conditions described above.

40) Enantioenriched compounds of formula (IX) can be prepared byreduction of Enantioenriched compounds of formula (III) or (VI).Suitable reagents for the reaction include, but are not limited to metalhydride The reaction can be conducted neat or in a suitable solvent. Thereaction temperature could be from −50° C. to 150° C., preferablybetween −20° C. and 100° C. The reaction time is usually between 1 hourand 96 hours, preferably between 1 hour and 24 hours. The reduction ofsuch succinimides are known to proceed through one or severalintermediates of formula (XXIX), (XXX), (XXXI), (XXXIII) and ($$), whichmay be optionally isolated.

41) Enantioenriched Compounds of formula (I″) wherein P is hydroxyl,C₁-C₆alkoxy, N-pyrrolyl, N-imidazolyl, N-1,2-4-triazolyl,N-benzotriazolyl or C₁-C₆alkylsulfinyl can be obtained by carrying out aBaeyer-Villiger oxidation reaction on enantioenriched compounds offormula (I′) wherein P is an optionally substituted aryl or anoptionally substituted heteroaryl. Suitable reagents for the reactioninclude, but are not limited to m-chloro peroxybenzoic acid, trifluoroperoxyacetic acid and peroxy sulfuric acid. The reaction can beconducted neat or in a suitable solvent. The reaction temperature couldbe from −50° C. to 150° C., preferably between −20° C. and 100° C. Thereaction time is usually between 1 hour and 96 hours, preferably between1 hour and 24 hours.

In the above schemes a leaving group may before example a halogen,C₁-C₈alkoxy, C₁-C₈alkylsulfonyloxy, C₁-C₈haloalkylsulfonyloxy, C₁-C₅arylsulfonyloxy, optionally substituted C₁-C₈arylsulfonyloxy (aryl ispreferably phenyl), diazonium salts (e.g. X^(B) is —N₂+Cl⁻, —N₂ ⁺BF₄ ⁻,—N₂ ⁺Br⁻, —N₂ ⁺PF₆ ⁻), phosphonate esters (e.g. —OP(O)(OR)₂, wherein Ris methyl or ethyl), preferably bromo, iodo, chloro,trifluoromethylsulfoxy, p-toluenesulfoxy, diazonium chloride.

In the above schemes, where a reaction condition, e.g. temperature,time, concentration, is given as a range, e.g. value X to value Y, theskilled person will understand that these values serve as guidelines andthat it may be possible to perform the reactions outside the givenvalues. In addition, where such ranges are given, in each case theseinclude separate disclosures of “at least X”, and “Y or less”. Forexample a range of 50° C. to 150° C. includes s disclosure of “at least50° C.” and a disclosure of “150° C. or less”.

The following tables A to M illustrate compounds relating to theinvention. In the compounds disclosed in Tables A to M thestereochemistry at * corresponds to that of formula II.

TABLE A Compounds of formula A (A)

Comp No. Q2 B2 Q4 1 Cl C—Cl Cl 2 Cl C—H Cl 3 CF₃ C—H CF₃ 4 Cl C—H CF₃ 5Br C—H CF₃ 6 Cl C—F H 7 F C—Cl H 8 Cl C—Cl H 9 Cl C—F Cl 10 Cl C—Br Cl11 Cl C—I Cl 12 F C—F F 13 Cl C—H Br 14 Cl C—H F 15 Cl C—Cl CF₃ 16 CF₃C—Cl CF₃ 17 CF₃ C—H H 18 Cl N Cl 19 Cl N H 20 CF₃ N CF₃ 21 CF₃ N H

TABLE B Compounds of formula B (B)

Comp No. Q2 B2 Q4 1 Cl C—Cl Cl 2 Cl C—H Cl 3 CF₃ C—H CF₃ 4 Cl C—H CF₃ 5Br C—H CF₃ 6 Cl C—F H 7 F C—Cl H 8 Cl C—Cl H 9 Cl C—F Cl 10 Cl C—Br Cl11 Cl C—I Cl 12 F C—F F 13 Cl C—H Br 14 Cl C—H F 15 Cl C—Cl CF₃ 16 CF₃C—Cl CF₃ 17 CF₃ C—H H 18 Cl N Cl 19 Cl N H 20 CF₃ N CF₃ 21 CF₃ N H

TABLE C Compounds of formula C (C)

Comp No. Q2 B2 Q4 1 Cl C—Cl Cl 2 Cl C—H Cl 3 CF₃ C—H CF₃ 4 Cl C—H CF₃ 5Br C—H CF₃ 6 Cl C—F H 7 F C—Cl H 8 Cl C—Cl H 9 Cl C—F Cl 10 Cl C—Br Cl11 Cl C—I Cl 12 F C—F F 13 Cl C—H Br 14 Cl C—H F 15 Cl C—Cl CF₃ 16 CF₃C—Cl CF₃ 17 CF₃ C—H H 18 Cl N Cl 19 Cl N H 20 CF₃ N CF₃ 21 CF₃ N H

TABLE D Compounds of formula D (D)

Comp No. Q2 B2 Q4 1 Cl C—Cl Cl 2 Cl C—H Cl 3 CF₃ C—H CF₃ 4 Cl C—H CF₃ 5Br C—H CF₃ 6 Cl C—F H 7 F C—Cl H 8 Cl C—Cl H 9 Cl C—F Cl 10 Cl C—Br Cl11 Cl C—I Cl 12 F C—F F 13 Cl C—H Br 14 Cl C—H F 15 Cl C—Cl CF₃ 16 CF₃C—Cl CF₃ 17 CF₃ C—H H 18 Cl N Cl 19 Cl N H 20 CF₃ N CF₃ 21 CF₃ N H

TABLE E Compounds of formula E (E)

Comp No. Q2 B2 Q4 1 Cl C—Cl Cl 2 Cl C—H Cl 3 CF₃ C—H CF₃ 4 Cl C—H CF₃ 5Br C—H CF₃ 6 Cl C—F H 7 F C—Cl H 8 Cl C—Cl H 9 Cl C—F Cl 10 Cl C—Br Cl11 Cl C—I Cl 12 F C—F F 13 Cl C—H Br 14 Cl C—H F 15 Cl C—Cl CF₃ 16 CF₃C—Cl CF₃ 17 CF₃ C—H H 18 Cl N Cl 19 Cl N H 20 CF₃ N CF₃ 21 CF₃ N H

TABLE F Compounds of formula F (F)

Comp No. Q2 B2 Q4 1 Cl C—Cl Cl 2 Cl C—H Cl 3 CF₃ C—H CF₃ 4 Cl C—H CF₃ 5Br C—H CF₃ 6 Cl C—F H 7 F C—Cl H 8 Cl C—Cl H 9 Cl C—F Cl 10 Cl C—Br Cl11 Cl C—I Cl 12 F C—F F 13 Cl C—H Br 14 Cl C—H F 15 Cl C—Cl CF₃ 16 CF₃C—Cl CF₃ 17 CF₃ C—H H 18 Cl N Cl 19 Cl N H 20 CF₃ N CF₃ 21 CF₃ N H

TABLE G Compounds of formula G (G)

Comp No. Q2 B2 Q4 1 Cl C—Cl Cl 2 Cl C—H Cl 3 CF₃ C—H CF₃ 4 Cl C—H CF₃ 5Br C—H CF₃ 6 Cl C—F H 7 F C—Cl H 8 Cl C—Cl H 9 Cl C—F Cl 10 Cl C—Br Cl11 Cl C—I Cl 12 F C—F F 13 Cl C—H Br 14 Cl C—H F 15 Cl C—Cl CF₃ 16 CF₃C—Cl CF₃ 17 CF₃ C—H H 18 Cl N Cl 19 Cl N H 20 CF₃ N CF₃ 21 CF₃ N H

TABLE H Compounds of formula H

(H)Table H discloses 630 compounds of formula H, wherein Q², B², Q⁴ and Phave the values as defined in Table X.

TABLE J Compounds of formula J

(J)Table J discloses 630 compounds of formula J, wherein Q², B², Q⁴ and Phave the values as defined in Table X.

TABLE K Compounds of formula K

(K)Table K discloses 630 compounds of formula K, wherein Q², B², Q⁴ and Phave the values as defined in Table X.

TABLE L Compounds of formula L

(L)Table L discloses 630 compounds of formula L, wherein Q², B², Q⁴ and Phave the values as defined in Table X.

TABLE M Compounds of formula M

(M)Table M discloses 630 compounds of formula M, wherein Q², B², Q⁴ and Phave the values as defined in Table X.

TABLE X Q2 B2 Q4 P X.1 Cl C—Cl Cl P1 X.2 Cl C—H Cl P1 X.3 CF₃ C—H CF₃ P1X.4 Cl C—H CF₃ P1 X.5 Br C—H CF₃ P1 X.6 Cl C—F H P1 X.7 F C—Cl H P1 X.8Cl C—Cl H P1 X.9 Cl C—F Cl P1 X.10 Cl C—Br Cl P1 X.11 Cl C—I Cl P1 X.12F C—F F P1 X.13 Cl C—H Br P1 X.14 Cl C—H F P1 X.15 Cl C—Cl CF3 P1 X.16CF3 C—Cl CF3 P1 X.17 CF3 C—H H P1 X.18 Cl C—Cl Cl P2 X.19 Cl C—H Cl P2X.20 CF₃ C—H CF₃ P2 X.21 Cl C—H CF₃ P2 X.22 Br C—H CF₃ P2 X.23 Cl C—F HP2 X.24 F C—Cl H P2 X.25 Cl C—Cl H P2 X.26 Cl C—F Cl P2 X.27 Cl C—Br ClP2 X.28 Cl C—I Cl P2 X.29 F C—F F P2 X.30 Cl C—H Br P2 X.31 Cl C—H F P2X.32 Cl C—Cl CF3 P2 X.33 CF3 C—Cl CF3 P2 X.34 CF3 C—H H P2 X.35 Cl C—ClCl P3 X.36 Cl C—H Cl P3 X.37 CF₃ C—H CF₃ P3 X.38 Cl C—H CF₃ P3 X.39 BrC—H CF₃ P3 X.40 Cl C—F H P3 X.41 F C—Cl H P3 X.42 Cl C—Cl H P3 X.43 ClC—F Cl P3 X.44 Cl C—Br Cl P3 X.45 Cl C—I Cl P3 X.46 F C—F F P3 X.47 ClC—H Br P3 X.48 Cl C—H F P3 X.49 Cl C—Cl CF3 P3 X.50 CF3 C—Cl CF3 P3 X.51CF3 C—H H P3 X.52 Cl C—Cl Cl P4 X.53 Cl C—H Cl P4 X.54 CF₃ C—H CF₃ P4X.55 Cl C—H CF₃ P4 X.56 Br C—H CF₃ P4 X.57 Cl C—F H P4 X.58 F C—Cl H P4X.59 Cl C—Cl H P4 X.60 Cl C—F Cl P4 X.61 Cl C—Br Cl P4 X.62 Cl C—I Cl P4X.63 F C—F F P4 X.64 Cl C—H Br P4 X.65 Cl C—H F P4 X.66 Cl C—Cl CF3 P4X.67 CF3 C—Cl CF3 P4 X.68 CF3 C—H H P4 X.69 Cl C—Cl Cl P5 X.70 Cl C—H ClP5 X.71 CF₃ C—H CF₃ P5 X.72 Cl C—H CF₃ P5 X.73 Br C—H CF₃ P5 X.74 Cl C—FH P5 X.75 F C—Cl H P5 X.76 Cl C—Cl H P5 X.77 Cl C—F Cl P5 X.78 Cl C—BrCl P5 X.79 Cl C—I Cl P5 X.80 F C—F F P5 X.81 Cl C—H Br P5 X.82 Cl C—H FP5 X.83 Cl C—Cl CF3 P5 X.84 CF3 C—Cl CF3 P5 X.85 CF3 C—H H P5 X.86 ClC—Cl Cl P6 X.87 Cl C—H Cl P6 X.88 CF₃ C—H CF₃ P6 X.89 Cl C—H CF₃ P6 X.90Br C—H CF₃ P6 X.91 Cl C—F H P6 X.92 F C—Cl H P6 X.93 Cl C—Cl H P6 X.94Cl C—F Cl P6 X.95 Cl C—Br Cl P6 X.96 Cl C—I Cl P6 X.97 F C—F F P6 X.98Cl C—H Br P6 X.99 Cl C—H F P6 X.100 Cl C—Cl CF3 P6 X.101 CF3 C—Cl CF3 P6X.102 CF3 C—H H P6 X.103 Cl C—Cl Cl P7 X.104 Cl C—H Cl P7 X.105 CF₃ C—HCF₃ P7 X.106 Cl C—H CF₃ P7 X.107 Br C—H CF₃ P7 X.108 Cl C—F H P7 X.109 FC—Cl H P7 X.110 Cl C—Cl H P7 X.111 Cl C—F Cl P7 X.112 Cl C—Br Cl P7X.113 Cl C—I Cl P7 X.114 F C—F F P7 X.115 Cl C—H Br P7 X.116 Cl C—H F P7X.117 Cl C—Cl CF3 P7 X.118 CF3 C—Cl CF3 P7 X.119 CF3 C—H H P7 X.120 ClC—Cl Cl P8 X.121 Cl C—H Cl P8 X.122 CF₃ C—H CF₃ P8 X.123 Cl C—H CF₃ P8X.124 Br C—H CF₃ P8 X.125 Cl C—F H P8 X.126 F C—Cl H P8 X.127 Cl C—Cl HP8 X.128 Cl C—F Cl P8 X.129 Cl C—Br Cl P8 X.130 Cl C—I Cl P8 X.131 F C—FF P8 X.132 Cl C—H Br P8 X.133 Cl C—H F P8 X.134 Cl C—Cl CF3 P8 X.135 CF3C—Cl CF3 P8 X.136 CF3 C—H H P8 X.137 Cl C—Cl Cl P9 X.138 Cl C—H Cl P9X.139 CF₃ C—H CF₃ P9 X.140 Cl C—H CF₃ P9 X.141 Br C—H CF₃ P9 X.142 ClC—F H P9 X.143 F C—Cl H P9 X.144 Cl C—Cl H P9 X.145 Cl C—F Cl P9 X.146Cl C—Br Cl P9 X.147 Cl C—I Cl P9 X.148 F C—F F P9 X.149 Cl C—H Br P9X.150 Cl C—H F P9 X.151 Cl C—Cl CF3 P9 X.152 CF3 C—Cl CF3 P9 X.153 CF3C—H H P9 X.154 Cl C—Cl Cl P10 X.155 Cl C—H Cl P10 X.156 CF₃ C—H CF₃ P10X.157 Cl C—H CF₃ P10 X.158 Br C—H CF₃ P10 X.159 Cl C—F H P10 X.160 FC—Cl H P10 X.161 Cl C—Cl H P10 X.162 Cl C—F Cl P10 X.163 Cl C—Br Cl P10X.164 Cl C—I Cl P10 X.165 F C—F F P10 X.166 Cl C—H Br P10 X.167 Cl C—H FP10 X.168 Cl C—Cl CF3 P10 X.169 CF3 C—Cl CF3 P10 X.170 CF3 C—H H P10X.171 Cl C—Cl Cl P11 X.172 Cl C—H Cl P11 X.173 CF₃ C—H CF₃ P11 X.174 ClC—H CF₃ P11 X.175 Br C—H CF₃ P11 X.176 Cl C—F H P11 X.177 F C—Cl H P11X.178 Cl C—Cl H P11 X.179 Cl C—F Cl P11 X.180 Cl C—Br Cl P11 X.181 ClC—I Cl P11 X.182 F C—F F P11 X.183 Cl C—H Br P11 X.184 Cl C—H F P11X.185 Cl C—Cl CF3 P11 X.186 CF3 C—Cl CF3 P11 X.187 CF3 C—H H P11 X.188Cl C—Cl Cl P12 X.187 Cl C—H Cl P12 X.190 CF₃ C—H CF₃ P12 X.191 Cl C—HCF₃ P12 X.192 Br C—H CF₃ P12 X.193 Cl C—F H P12 X.194 F C—Cl H P12 X.195Cl C—Cl H P12 X.196 Cl C—F Cl P12 X.197 Cl C—Br Cl P12 X.198 Cl C—I ClP12 X.199 F C—F F P12 X.200 Cl C—H Br P12 X.201 Cl C—H F P12 X.202 ClC—Cl CF3 P12 X.203 CF3 C—Cl CF3 P12 X.204 CF3 C—H H P12 X.205 Cl C—Cl ClP13 X.206 Cl C—H Cl P13 X.207 CF₃ C—H CF₃ P13 X.208 Cl C—H CF₃ P13 X.209Br C—H CF₃ P13 X.210 Cl C—F H P13 X.211 F C—Cl H P13 X.212 Cl C—Cl H P13X.213 Cl C—F Cl P13 X.214 Cl C—Br Cl P13 X.215 Cl C—I Cl P13 X.216 F C—FF P13 X.217 Cl C—H Br P13 X.218 Cl C—H F P13 X.219 Cl C—Cl CF3 P13 X.220CF3 C—Cl CF3 P13 X.221 CF3 C—H H P13 X.222 Cl C—Cl Cl P14 X.223 Cl C—HCl P14 X.224 CF₃ C—H CF₃ P14 X.225 Cl C—H CF₃ P14 X.226 Br C—H CF₃ P14X.227 Cl C—F H P14 X.228 F C—Cl H P14 X.229 Cl C—Cl H P14 X.230 Cl C—FCl P14 X.231 Cl C—Br Cl P14 X.232 Cl C—I Cl P14 X.233 F C—F F P14 X.234Cl C—H Br P14 X.235 Cl C—H F P14 X.236 Cl C—Cl CF3 P14 X.237 CF3 C—ClCF3 P14 X.238 CF3 C—H H P14 X.239 Cl C—Cl Cl P15 X.240 Cl C—H Cl P15X.241 CF₃ C—H CF₃ P15 X.242 Cl C—H CF₃ P15 X.243 Br C—H CF₃ P15 X.244 ClC—F H P15 X.245 F C—Cl H P15 X.246 Cl C—Cl H P15 X.247 Cl C—F Cl P15X.248 Cl C—Br Cl P15 X.249 Cl C—I Cl P15 X.250 F C—F F P15 X.251 Cl C—HBr P15 X.252 Cl C—H F P15 X.253 Cl C—Cl CF3 P15 X.254 CF3 C—Cl CF3 P15X.255 CF3 C—H H P15 X.256 Cl C—Cl Cl P16 X.257 Cl C—H Cl P16 X.258 CF₃C—H CF₃ P16 X.259 Cl C—H CF₃ P16 X.260 Br C—H CF₃ P16 X.261 Cl C—F H P16X.262 F C—Cl H P16 X.263 Cl C—Cl H P16 X.264 Cl C—F Cl P16 X.265 Cl C—BrCl P16 X.266 Cl C—I Cl P16 X.267 F C—F F P16 X.268 Cl C—H Br P16 X.269Cl C—H F P16 X.270 Cl C—Cl CF3 P16 X.271 CF3 C—Cl CF3 P16 X.272 CF3 C—HH P16 X.273 Cl C—Cl Cl P17 X.274 Cl C—H Cl P17 X.275 CF₃ C—H CF₃ P17X.276 Cl C—H CF₃ P17 X.277 Br C—H CF₃ P17 X.278 Cl C—F H P17 X.279 FC—Cl H P17 X.280 Cl C—Cl H P17 X.281 Cl C—F Cl P17 X.282 Cl C—Br Cl P17X.283 Cl C—I Cl P17 X.284 F C—F F P17 X.285 Cl C—H Br P17 X.286 Cl C—H FP17 X.287 Cl C—Cl CF3 P17 X.288 CF3 C—Cl CF3 P17 X.289 CF3 C—H H P17X.290 Cl C—Cl Cl P18 X.291 Cl C—H Cl P18 X.292 CF₃ C—H CF₃ P18 X.293 ClC—H CF₃ P18 X.294 Br C—H CF₃ P18 X.295 Cl C—F H P18 X.296 F C—Cl H P18X.297 Cl C—Cl H P18 X.298 Cl C—F Cl P18 X.299 Cl C—Br Cl P18 X.300 ClC—I Cl P18 X.301 F C—F F P18 X.302 Cl C—H Br P18 X.303 Cl C—H F P18X.304 Cl C—Cl CF3 P18 X.305 CF3 C—Cl CF3 P18 X.306 CF3 C—H H P18 X.307Cl C—Cl Cl P19 X.308 Cl C—H Cl P19 X.309 CF₃ C—H CF₃ P19 X.310 Cl C—HCF₃ P19 X.311 Br C—H CF₃ P19 X.312 Cl C—F H P19 X.313 F C—Cl H P19 X.314Cl C—Cl H P19 X.315 Cl C—F Cl P19 X.316 Cl C—Br Cl P19 X.317 Cl C—I ClP19 X.318 F C—F F P19 X.319 Cl C—H Br P19 X.320 Cl C—H F P19 X.321 ClC—Cl CF3 P19 X.322 CF3 C—Cl CF3 P19 X.323 CF3 C—H H P19 X.324 Cl C—Cl ClP20 X.325 Cl C—H Cl P20 X.326 CF₃ C—H CF₃ P20 X.327 Cl C—H CF₃ P20 X.328Br C—H CF₃ P20 X.329 Cl C—F H P20 X.330 F C—Cl H P20 X.331 Cl C—Cl H P20X.332 Cl C—F Cl P20 X.333 Cl C—Br Cl P20 X.334 Cl C—I Cl P20 X.335 F C—FF P20 X.336 Cl C—H Br P20 X.337 Cl C—H F P20 X.338 Cl C—Cl CF3 P20 X.339CF3 C—Cl CF3 P20 X.340 CF3 C—H H P20 X.341 Cl C—Cl Cl P21 X.342 Cl C—HCl P21 X.343 CF₃ C—H CF₃ P21 X.344 Cl C—H CF₃ P21 X.345 Br C—H CF₃ P21X.346 Cl C—F H P21 X.347 F C—Cl H P21 X.348 Cl C—Cl H P21 X.349 Cl C—FCl P21 X.350 Cl C—Br Cl P21 X.351 Cl C—I Cl P21 X.352 F C—F F P21 X.353Cl C—H Br P21 X.354 Cl C—H F P21 X.355 Cl C—Cl CF3 P21 X.356 CF3 C—ClCF3 P21 X.357 CF3 C—H H P21 X.358 Cl C—Cl Cl P22 X.359 Cl C—H Cl P22X.360 CF₃ C—H CF₃ P22 X.361 Cl C—H CF₃ P22 X.362 Br C—H CF₃ P22 X.363 ClC—F H P22 X.364 F C—Cl H P22 X.365 Cl C—Cl H P22 X.366 Cl C—F Cl P22X.367 Cl C—Br Cl P22 X.368 Cl C—I Cl P22 X.369 F C—F F P22 X.370 Cl C—HBr P22 X.371 Cl C—H F P22 X.372 Cl C—Cl CF3 P22 X.373 CF3 C—Cl CF3 P22X.374 CF3 C—H H P22 X.375 Cl C—Cl Cl P23 X.376 Cl C—H Cl P23 X.377 CF₃C—H CF₃ P23 X.378 Cl C—H CF₃ P23 X.379 Br C—H CF₃ P23 X.380 Cl C—F H P23X.381 F C—Cl H P23 X.382 Cl C—Cl H P23 X.383 Cl C—F Cl P23 X.384 Cl C—BrCl P23 X.385 Cl C—I Cl P23 X.386 F C—F F P23 X.387 Cl C—H Br P23 X.388Cl C—H F P23 X.389 Cl C—Cl CF3 P23 X.390 CF3 C—Cl CF3 P23 X.391 CF3 C—HH P23 X.392 Cl C—Cl Cl P24 X.393 Cl C—H Cl P24 X.394 CF₃ C—H CF₃ P24X.395 Cl C—H CF₃ P24 X.396 Br C—H CF₃ P24 X.397 Cl C—F H P24 X.398 FC—Cl H P24 X.399 Cl C—Cl H P24 X.400 Cl C—F Cl P24 X.401 Cl C—Br Cl P24X.402 Cl C—I Cl P24 X.403 F C—F F P24 X.404 Cl C—H Br P24 X.405 Cl C—H FP24 X.406 Cl C—Cl CF3 P24 X.407 CF3 C—Cl CF3 P24 X.408 CF3 C—H H P24X.409 Cl C—Cl Cl P25 X.410 Cl C—H Cl P25 X.411 CF₃ C—H CF₃ P25 X.412 ClC—H CF₃ P25 X.413 Br C—H CF₃ P25 X.414 Cl C—F H P25 X.415 F C—Cl H P25X.416 Cl C—Cl H P25 X.417 Cl C—F Cl P25 X.418 Cl C—Br Cl P25 X.419 ClC—I Cl P25 X.420 F C—F F P25 X.421 Cl C—H Br P25 X.422 Cl C—H F P25X.423 Cl C—Cl CF3 P25 X.424 CF3 C—Cl CF3 P25 X.425 CF3 C—H H P25 X.426Cl C—Cl Cl P26 X.427 Cl C—H Cl P26 X.428 CF₃ C—H CF₃ P26 X.429 Cl C—HCF₃ P26 X.430 Br C—H CF₃ P26 X.431 Cl C—F H P26 X.432 F C—Cl H P26 X.433Cl C—Cl H P26 X.434 Cl C—F Cl P26 X.435 Cl C—Br Cl P26 X.436 Cl C—I ClP26 X.437 F C—F F P26 X.438 Cl C—H Br P26 X.439 Cl C—H F P26 X.440 ClC—Cl CF3 P26 X.441 CF3 C—Cl CF3 P26 X.442 CF3 C—H H P26 X.443 Cl C—Cl ClP27 X.444 Cl C—H Cl P27 X.445 CF₃ C—H CF₃ P27 X.446 Cl C—H CF₃ P27 X.447Br C—H CF₃ P27 X.448 Cl C—F H P27 X.449 F C—Cl H P27 X.450 Cl C—Cl H P27X.451 Cl C—F Cl P27 X.452 Cl C—Br Cl P27 X.453 Cl C—I Cl P27 X.454 F C—FF P27 X.455 Cl C—H Br P27 X.456 Cl C—H F P27 X.457 Cl C—Cl CF3 P27 X.458CF3 C—Cl CF3 P27 X.459 CF3 C—H H P27 X.460 Cl C—Cl Cl P28 X.461 Cl C—HCl P28 X.462 CF₃ C—H CF₃ P28 X.463 Cl C—H CF₃ P28 X.464 Br C—H CF₃ P28X.465 Cl C—F H P28 X.466 F C—Cl H P28 X.467 Cl C—Cl H P28 X.468 Cl C—FCl P28 X.469 Cl C—Br Cl P28 X.470 Cl C—I Cl P28 X.471 F C—F F P28 X.472Cl C—H Br P28 X.473 Cl C—H F P28 X.474 Cl C—Cl CF3 P28 X.475 CF3 C—ClCF3 P28 X.476 CF3 C—H H P28 X.477 Cl C—Cl Cl P29 X.478 Cl C—H Cl P29X.479 CF₃ C—H CF₃ P29 X.480 Cl C—H CF₃ P29 X.481 Br C—H CF₃ P29 X.482 ClC—F H P29 X.483 F C—Cl H P29 X.484 Cl C—Cl H P29 X.485 Cl C—F Cl P29X.486 Cl C—Br Cl P29 X.487 Cl C—I Cl P29 X.488 F C—F F P29 X.489 Cl C—HBr P29 X.490 Cl C—H F P29 X.491 Cl C—Cl CF3 P29 X.492 CF3 C—Cl CF3 P29X.493 CF3 C—H H P29 X.494 Cl C—Cl Cl P30 X.495 Cl C—H Cl P30 X.496 CF₃C—H CF₃ P30 X.497 Cl C—H CF₃ P30 X.498 Br C—H CF₃ P30 X.499 Cl C—F H P30X.500 F C—Cl H P30 X.501 Cl C—Cl H P30 X.502 Cl C—F Cl P30 X.503 Cl C—BrCl P30 X.504 Cl C—I Cl P30 X.505 F C—F F P30 X.506 Cl C—H Br P30 X.507Cl C—H F P30 X.508 Cl C—Cl CF3 P30 X.509 CF3 C—Cl CF3 P30 X.510 CF3 C—HH P30 X.511 Cl N Cl P1 X.512 Cl N H P1 X.513 CF₃ N CF₃ P1 X.514 CF₃ N HP1 X.515 Cl N Cl P2 X.516 Cl N H P2 X.517 CF3 N CF3 P2 X.518 CF3 N H P2X.519 Cl N Cl P3 X.520 Cl N H P3 X.521 CF3 N CF3 P3 X.522 CF3 N H P3X.523 Cl N Cl P4 X.524 Cl N H P4 X.525 CF3 N CF3 P4 X.526 CF3 N H P4X.527 Cl N Cl P5 X.528 Cl N H P5 X.529 CF3 N CF3 P5 X.530 CF3 N H P5X.531 Cl N Cl P6 X.532 Cl N H P6 X.533 CF3 N CF3 P6 X.534 CF3 N H P6X.535 Cl N Cl P7 X.536 Cl N H P7 X.537 CF3 N CF3 P7 X.538 CF3 N H P7X.539 Cl N Cl P8 X.540 Cl N H P8 X.541 CF3 N CF3 P8 X.542 CF3 N H P8X.543 Cl N Cl P9 X.544 Cl N H P9 X.545 CF3 N CF3 P9 X.546 CF3 N H P9X.547 Cl N Cl P10 X.548 Cl N H P10 X.549 CF3 N CF3 P10 X.550 CF3 N H P10X.551 Cl N Cl P11 X.552 Cl N H P11 X.553 CF3 N CF3 P11 X.554 CF3 N H P11X.555 Cl N Cl P12 X.556 Cl N H P12 X.557 CF3 N CF3 P12 X.558 CF3 N H P12X.559 Cl N Cl P13 X.560 Cl N H P13 X.561 CF3 N CF3 P13 X.562 CF3 N H P13X.563 Cl N Cl P14 X.564 Cl N H P14 X.565 CF3 N CF3 P14 X.566 CF3 N H P14X.567 Cl N Cl P15 X.568 Cl N H P15 X.569 CF3 N CF3 P15 X.570 CF3 N H P15X.571 Cl N Cl P16 X.572 Cl N H P16 X.573 CF3 N CF3 P16 X.574 CF3 N H P16X.575 Cl N Cl P17 X.576 Cl N H P17 X.577 CF3 N CF3 P17 X.578 CF3 N H P17X.579 Cl N Cl P18 X.580 Cl N H P18 X.581 CF3 N CF3 P18 X.582 CF3 N H P18X.583 Cl N Cl P19 X.584 Cl N H P19 X.585 CF3 N CF3 P19 X.586 CF3 N H P19X.587 Cl N Cl P20 X.588 Cl N H P20 X.589 CF3 N CF3 P20 X.590 CF3 N H P20X.591 Cl N Cl P21 X.592 Cl N H P21 X.593 CF3 N CF3 P21 X.594 CF3 N H P21X.595 Cl N Cl P22 X.596 Cl N H P22 X.597 CF3 N CF3 P22 X.598 CF3 N H P22X.599 Cl N Cl P23 X.600 Cl N H P23 X.601 CF3 N CF3 P23 X.602 CF3 N H P23X.603 Cl N Cl P24 X.604 Cl N H P24 X.605 CF3 N CF3 P24 X.606 CF3 N H P24X.607 Cl N Cl P25 X.608 Cl N H P25 X.609 CF3 N CF3 P25 X.610 CF3 N H P25X.611 Cl N Cl P26 X.612 Cl N H P26 X.613 CF3 N CF3 P26 X.614 CF3 N H P26X.615 Cl N Cl P27 X.616 Cl N H P27 X.617 CF3 N CF3 P27 X.618 CF3 N H P27X.619 Cl N Cl P28 X.620 Cl N H P28 X.621 CF3 N CF3 P28 X.622 CF3 N H P28X.623 Cl N Cl P29 X.624 Cl N H P29 X.625 CF3 N CF3 P29 X.626 CF3 N H P29X.627 Cl N Cl P30 X.628 Cl N H P30 X.629 CF3 N CF3 P30 X.630 CF3 N H P30The values of P1 to P30 in Table X are shown in Table P.

TABLE P P1  —OCH₃ P2  —OCH₂CH₃ P3  —OtBu P4  —NMe₂ P5 

P6 

P7 

P8 

P9 

P10 OPh P11 Ph P12

P13

P14

P15 tBu P16

P17

P18

P19

P20

P21

P22

P23

P24

P25 —CH(CH₃)₂ P26

P27

P28

P29 OCH₂Ph P30 OH

PREPARATION EXAMPLES

The following abbreviations were used in this section: s=singlet;bs=broad singlet; d=doublet; dd=double doublet; dt=double triplet;t=triplet, tt=triple triplet, q=quartet, sept=septet; m=multiplet;Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; M.p.=melting point;RT=retention time, [M+H]⁺=molecular mass of the molecular cation,[M−H]⁻=molecular mass of the molecular anion.

The following LC-MS methods were used to characterize the compounds:

Method C MS ZQ Mass Spectrometer from Waters (single quadrupole massspectrometer), ionization method: electrospray, polarity: positiveionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00,source temperature (° C.) 100, desolvation temperature (° C.) 200, conegas flow (L/Hr) 200, desolvation gas flow (L/Hr) 250, mass range: 150 to800 Da. LC 1100er Series HPLC from Agilent: quaternary pump, heatedcolumn compartment and diode-array detector. Column: Waters Atlantisdc18, length (mm) 20, internal diameter (mm) 3, particle size (μm) 3,temperature (° C.) 40, DAD wavelength range (nm): 200 to 500, solventgradient: A = 0.1% v/v formic acid in water and B = 0.1% v/v formic acidin acetonitrile. Time (min) A % B % Flow (ml/min) 0.0 90 10 1.7 5.5 0.0100 1.7 5.8 0.0 100 1.7 5.9 90 10 1.7

Method D MS ZMD Mass Spectrometer from Waters (single quadrupole massspectrometer), ionization method: electrospray, polarity: positiveionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00,source temperature (° C.) 150, desolvation temperature (° C.) 320, conegas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 150 to800 Da. LC Alliance 2795 LC HPLC from Waters: quaternary pump, heatedcolumn compartment and diode-array detector. Column: Waters Atlantisdc18, length (mm) 20, internal diameter (mm) 3, particle size (μm) 3,temperature (° C.) 40, DAD wavelength range (nm): 200 to 500, solventgradient: A = 0.1% v/v formic acid in water and B = 0.1% v/v formic acidin acetonitrile. Time (min) A % B % Flow (ml/min) 0.0 80 20 1.7 2.5 0.0100 1.7 2.8 0.0 100 1.7 2.9 80 20 1.7

Method F MS ZQ Mass Spectrometer from Waters (single quadrupole massspectrometer), ionization method: electrospray, polarity: negativeionization, capillary (kV) 3.00, cone (V) 45.00, source temperature (°C.) 100, desolvation temperature (° C.) 250, cone gas flow (L/Hr) 50,desolvation gas flow (L/Hr) 400, mass range: 150 to 1000 Da. LC HP 1100HPLC from Agilent: solvent degasser, binary pump, heated columncompartment and diode-array detector. Column: Phenomenex Gemini C18,length (mm) 30, internal diameter (mm) 3, particle size (μm) 3,temperature (° C.) 60, DAD wavelength range (nm): 200 to 500, solventgradient: A = 0.05% v/v formic acid in water and B = 0.04% v/v formicacid in acetonitrile/methanol (4:1). Time (min) A % B % Flow (ml/min)0.0 95 5.0 1.7 2.0 0.0 100 1.7 2.8 0.0 100 1.7 2.9 95 5.0 1.7 3.1 95 51.7

Example 1 Preparation of enantioenritched4-[(3R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoicacid tert-butyl ester

Potassium cyanide (6.465 g, 99.283 mmol) and acetone cyanohydrin (23.9ml, 261.272 mmol) were added to a solution of4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoicacid tert-butyl ester (40.000 g, 87.091 mmol) in toluene (600.0 ml). Tothis vigorously stirred suspension was added 9-anthrylmethyl quininiumchloride (7.200 g, 13.064 mmol). The reaction mixture was stirred at 60°C. for 2 hours and at room temperature during 63 hours. At this timewater was added and the reaction mixture was extracted withdichloromethane (3×). The crude product was purified by flashchromatography (0% to 5% ethyl acetate in cyclohexane) to afford4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoicacid tert-butyl ester (35.80 g, 67.6%) as a white amorphous solid.Chiral HPLC analysis (Chiralpack IB, Heptane:2-propanol=98:2 1 ml/min):retention time 8.11 minutes (minor enantiomer, 5%), 9.95 minutes (majorenantiomer, 95%)

¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, 1H), 7.78-7.72 (m, 2H), 7.48 (s, 2H),7.46-7.42 (m, 1H), 4.17 (d, 1H), 4.02 (d, 2H), 2.62 (s, 3H), 1.62 (s,9H)

Example 2 Preparation of 9-anthrylmethyl quinidinium chloride

A solution of 9-chloromethyl-anthracene (0.91 g, 1.3 eq, 0.40 mmol) andquinidine [CAS=56-54-2] (1 g, 0.38) in toluene (10 ml) was heated at 90°C. for 18 hours. The reaction mixture was filtered, washed withn-heptane. The solid was recrystallised from chloroform and n-heptane toafford the title product (1.69 g) as a yellow solid. Preparation of thiscompound is also reported in dissertation: contributions to theasymmetric catalysis of c-c couplings, and to the chemical induction ofcardiomyogenesis from embryonic stem cells, bianca seelig, universityköhl 2009.

Example 3 Preparation of enantioenritched4-[(3S)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoicacid tert-butyl ester

Potassium cyanide (0.021 g, 0.32 mmol) and acetone cyanohydrin (0.086mg, 1.01 mmol) were added to a solution tert-butyl4-[(E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzo(0.150 mg, 0.326 mmol) in toluene (1.0 ml). To this vigorously stirredsuspension was added 9-anthrylmethyl quinidinium chloride (0.054 g,0.098 mmol). The reaction mixture was stirred at 45° C. for 18 hours. Atthis time water was added and the reaction mixture was extracted withtoluene (3×). The crude product was purified by flash chromatography (0%to 5% ethyl acetate in cyclohexane) to afford tert-butyl4-[(3S)-3-cyano-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-butanoyl]-2-methyl-benzoate(0.080 g, 50%) as a white foam.Chiral HPLC analysis (Chiralpack IB, Heptane:2-propanol=98:2 1 ml/min):retention time 7.64 minutes (major enantiomer, 78.5%), 9.53 minutes(minor enantiomer, 21.5%). ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, 1H),7.78-7.72 (m, 2H), 7.48 (s, 2H), 7.46-7.42 (m, 1H), 4.17 (d, 1H), 4.02(d, 2H), 2.62 (s, 3H), 1.62 (s, 9H)

Example 4 Preparation of enantioenritched(3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine-2,5-dione

Hydrogen peroxide (aq. 30%, 2.0 mL) was added to sulfuric acid (96%,15.0 mL) slowly at <0° C. followed by tert-butyl4-[(3R)-3-cyano-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-butanoyl]-2-methyl-benzoate(600 mg) in dichloromethane (6.0 mL). The reaction mixture was stirredfor 30 min. at 0° C. The reaction mixture was added on ice, treated withsaturated aq. Na₂SO₃ and extracted with dichloromethane (3×). Thecombined organic phase were dried (Na₂SO₄), evaporated giving 1.03 g ofyellowish foam. It was dissolved in methanol (8 mL) and treated with 8Msodium hydroxide (3 mL). The reaction mixture was stirred at 30 min atRT, acidified with conc. HCl and extracted with dichloromethane. Theorganic phase was washed with water, NaHCO₃ (aq., sat.), water. It wasdried (Na₂SO₄) and evaporated giving the title compound as a white solid450 mg (70%).

¹H-NMR (400 MHz, CDCl₃): δ 3.49 (d, J=18.5 Hz), 3.25 (d, J=18.5 Hz),7.47 (s, 1H), 7.57 (s, 2H), 8.53 (bs, 1H) ppm.

¹³C-NMR (101 MHz, CDCl₃): δ 39.0, 56.8 (q, J=27 Hz), 123.7 (q, J=284Hz), 126.6), 130.14, 134.4, 136.0, 170.4, 171.6 ppm.

¹⁹F-NMR (377 MHz, CDCl₃): δ −71.6 ppm.

LC/MS (ES-): 310 (M−H)⁻, R_(t)=1.72 min

GC/MS (CI): 312 (M+H)⁺, R_(t)=6.25 min

m.p.=138-141° C.

Example 5 Preparation of(3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine

To a solution of3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine-2,5-dione (0.02 g)in dry THF (0.5 ml) were added sequentially BF₃ etherate (0.109 g, 6equiv.) and borane-THF complex 1M in THF (1.4 g, 24 equiv.) The reactionstirred at 40° C. for 18 h. After cooling to room temperature, HCl (aq.4M solution, 1 ml) was added to the mixture and heated for additional 30minutes at 40° C. After cooling to room temperature, the reactionmixture was washed with Et₂O. The aqueous phase was basified to pH-10with NaOH and extracted with ethyl acetate (3×). The combined ethylacetate extracts were dried (Na₂SO₄) and evaporated. The crude productwas purified by column chromatography (silica, eluent: AcOEt with 1%Et₃N and 1% MeOH) giving 3.5 mg (19%) of the title compound as acolorless solid.Chiral HPLC analysis (Chiralpack IA,Heptane:2-propanol:diethylamine=70:30:0.1, 1 ml/min): retention time5.15 minutes (minor enantiomer, <15%), 6.96 minutes (major enantiomer,>75%).

¹H-NMR (400 MHz, CDCl₃): δ=7.36 (t, 1H); 7.26 (d, 2H, 0.73 Hz); 3.76 (d,1H, 12.8 Hz); 3.32-3.21 (m, 2H); 3.10-3.01 (m, 1H); 2.60-2.51 (m, 1H);2.36-2.26 (m, 1H) ppm. LC/MS (ES-): 284 (M+H)⁺, R_(t)=1.07 min

Example 6 Preparation of enantioenritched(3R)-3-(3,5-dichlorophenyl)-1-methyl-3-(trifluoromethyl)pyrrolidine-2,5-dione

In a dried flask, under argon, to a solution of(3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine-2,5-dione (99mg) in dry DMF, was added potassium carbonate (0.117 g, 0.84 mmol),followed by iodomethane (0.1213 g, 0.84 mmol). The reaction mixture wasstirred for 2 hours at from temperature. Water was added to the reactionmixture and it was extracted with Et2O. The organic phase was washed onetime with HCl solution (0.5N), dried over Na2SO4 and evaporated invacuum to give 62 mg (60%) as a yellow oil

¹H-NMR (400 MHz, CDCl₃): δ 3.12 (s, 3H); 3.22 (d, 1H, J=18.3 Hz), 3.44(d, 1H, J=18 Hz), 7.45 (t, 1H), 7.58 (s, 2H), ppm.

GC/MS: RT=5.72 min; 326 (M+H)⁺

Example 7 Preparation of enantioenritched(3R)-3-(3,5-dichlorophenyl)-1-methyl-3-(trifluoromethyl)pyrrolidine

To a solution of(3R)-3-(3,5-dichlorophenyl)-1-methyl-3-(trifluoromethyl)pyrrolidine-2,5-dione(0.05 g) in dry THF (1 ml) were added sequentially BF₃ etherate (0.271g, 0.975 mmol, 6 equiv.) and borane-THF complex 1M in THF (3.4 g, 24equiv.) The reaction stirred at 40° C. for 18 h. After cooling to roomtemperature, HCl (aq. 4M solution, 1 ml) was added to the mixture andheated for additional 30 minutes at 40° C. After cooling to roomtemperature, the reaction mixture was washed with Et₂O. The aqueousphase was basified to pH˜10 with NaOH and extracted with ethyl acetate(3×). The combined ethyl acetate extracts were dried (Na₂SO₄) andevaporated giving the desired product 10 mg (21%).

¹H-NMR (400 MHz, CDCl₃): δ 7.62 (S, 2H); 7.39 (t, 1H); 3.74-3.68 (m,1H); 3.47-3.39 (m, 2H); 3.35-3.27 (m, 1H); 2.97 (s, 3H); 2.84-2.75 (m,1H); 2.60-2.52 (m, 1H);

LC/MS (ES-): 298 (M+H)⁺, R_(t)=1.14 min

Example 8 Preparation of(E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(2-furyl)but-2-en-1-one

A flask was charged with starting material 1-(2-furyl)ethanone (5.00 g),1-(3,5-dichlorophenyl)-2,2,2-trifluoro-ethanone (12.39 g), potassiumcarbonate (7.00 g), triethylamine (0.46 g) and 1,2-dichloroethane (50mL). The reaction mixture was stirred and heated to reflux for 12 hours.Then potassium carbonate (6.00 g) was added and heating was continuedfor another 12 hours. The reaction mixture was diluted withdichloromethane, washed with water (2×) and the organic phase was driedover Na₂SO₄ and evaporated. Purification of the crude product via columnchromatography (silica, n-heptane/ethyl acetate gradient) gave 10.8 g(71%) of the desired product.

¹H-NMR (400 MHz, CDCl₃): δ 7.66-7.64 (m, 1H); 7.42-7.39 (m, 2H); 7.26(d, 1H, J=3.7 Hz); 7.18 (d, 2H, J=1.47 Hz) ppm.

¹³C-NMR (101 MHz, CDCl₃): δ 176.5; 152.5; 147.7; 138.8 (q); 135.0;133.6; 129.5; 128.4 (q); 127.4; 122.1 (q); 119.5; 113.1 ppm.

25 ¹⁹F-NMR (377 MHz, CDCl₃): δ −67.09 ppm.

GC/MS (CI): 335 (M+H)⁺, R_(t)=5.73 min

m.p.=72-76° C.

Example 9 Preparation of enantioenritched2-(3,5-dichlorophenyl)-4-(2-furyl)-4-oxo-2-(trifluoromethyl)butanenitrile

To a solution of(E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(2-furyl)but-2-en-1-one(0.200 g, 0.597 mmol) in toluene (3 mL) were added(R)-[1-(9-anthrylmethyl)-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinolyl)methanolchloride (0.066 g, 0.119 mmol), acetone cyanohydrin (0.165 mL, 1.802mmol) and potassium carbonate (0.09206 g, 0.657 mmol) sequentially. Thereaction mixture was vigorously stirred at room temperature for 2 h. Atthis time aqueous solution of NH₄Cl was added and the reaction mixturewas extracted with AcOEt, dried (Na₂SO₄) and evaporated. Purification ofthe crude product via column chromatography (silica, n-heptane/ethylacetate gradient) gave 165 mg (76%) of the desired product as whitesemisolid.Chiral HPLC analysis (Chiralpack AS-R3, Acetonitrile:MeOH:Water=45:5:50,1 ml/min): retention time 56.73 minutes (minor enantiomer, 13.4%), 59.31minutes (major enantiomer, 86.6%). (The identity of the stereochemistrywas not determined. It is expected that the alternative isomer could beproduced in enantiomeric excess with use an appropriate catalyst withreversed stereochemistry.)

¹H-NMR (400 MHz, CDCl₃): δ 7.68-7.67 (m, 1H); 7.51 (s, 2H); 7.46 (t,1H); 7.30-7.27 (m, 1H); 6.64 (dd, 1H, J=1.83 Hz, J=3.67 Hz); 4.48 (d,1H, J=18.3 Hz); 3.89 (d, 1H, J=18.3 Hz) ppm

GC/MS (CI): 362 (M+H)⁺, R_(t)=6.60 min

Example 10 Preparation of enantioenritched3-cyano-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-butanoic acid

2-(3,5-dichlorophenyl)-4-(2-furyl)-4-oxo-2-(trifluoromethyl)butanenitrile(0.150 g, 0.414 mmol) was dissolved in a mixture of dichloromethane,acetonitrile and water (1:1:2). Sodium periodate (0.627 g, 2.900 mmol)was added, followed by ruthenium chloride hydrate (0.003 g, 0.035 mmol).The reaction mixture was stirred at room temperature overnight. Thereaction was diluted with CH2Cl2; the organic phase was washed with H₂Oand dried over Na2SO4 giving 53 mg of violet solid.

¹H-NMR (400 MHz, CDCl₃): δ 7.49 (s, 1H); 7.46 (s, 2H); 3.42 (s, 2H) ppm

LC/MS: R_(t)=1.83 min; 310 (M−H)⁻,

Example 11 Preparation of(E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-pyrrol-1-yl-but-2-en-1-one

A suspension of sodium hydride (0.117 g) in 1,2-dimethoxyethane (5 ml)was cooled to 0° C. and a solution of2-diethoxyphosphoryl-1-pyrrol-1-yl-ethanone (0.754 g) in1,2-dimethoxyethane (2 ml) was added drop-wise and stirred for 20 min.To the reaction mixture was added drop-wise a solution of1-(3,5-dichlorophenyl)-2,2,2-trifluoro-ethanone (0.503 g) in1,2-dimethoxyethane (2 ml). The reaction was stirred for a further 30min at 0° C., then allowed to warm to RT and stirred for a further 2 h.The reaction mixture was quenched by cautious addition of saturatedNH₄Cl(10 ml) solution over ice and extracted with ethyl acetate (3×15ml). The combined organics were passed through a PTFE membrane andconcentrated in vacuo to give a turbid orange oil, which was taken up intoluene and purified by column-chromatography on a pre-packed silicacolumn eluting with heptanes/ethyl acetate to give the title compound asa pale yellow oil (0.313 g)

¹H-NMR: (400 MHz, CDCl₃) δ_(H) ppm 7.40 (m, 2H), 7.20 (m, 3H), 7.18-7.19(m, 1H), 6.33-6.35 (m, 2H).

Example 12 Preparation of enantioenritched2-(3,5-dichlorophenyl)-4-oxo-4-pyrrol-1-yl-2-(trifluoromethyl)-butanenitrile

To a suspension of potassium carbonate (0.144 g) and(R)-(6-methoxy-4-quinolyl)-[(2S,4S,5R)-1-[(2,3,4,5,6-pentafluorophenyl)methyl]-5-vinyl-quinuclidin-1-ium-2-yl]methanolbromide (0.126 g) in toluene (4 ml) was added a solution of(E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-pyrrol-1-yl-but-2-en-1-one(0.313 g) in toluene (2 ml) followed by2-hydroxy-2-methyl-propanenitrile (100 μl) in toluene (2 ml). Thereaction mixture was heated to 45° C. overnight before potassium cyanide(0.077 g), a drop of water and a further aliquot of the2-hydroxy-2-methyl-propanenitrile (100 μl) were added and the reactionmixture heated to 60° C. for a further 4 h. The reaction was poured ontosaturated NH₄Cl solution and extracted with dichloromethane (3×25 ml).The combined organics were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give a dark amber gum, which was purified bycolumn-chromatography on a pre-packed silica column eluting withheptanes/ethyl acetate to give the title compound as a pale yellow oil(0.084 g). Chiral HPLC analysis (Chiralpack IA,Heptane:isopropanol=95:5, 1 ml/min): retention time 6.09 minutes (minorenantiomer, 34%), 6.96 minutes (major enantiomer, 66%). (The identity ofthe stereochemistry was not determined. It is expected that thealternative isomer could be produced in enantiomeric excess with use ofan appropriate catalyst with reversed stereochemistry)

¹H-NMR (400 MHz, CDCl₃) δ_(H) ppm 7.48-7.51 (m, 2H), 7.45-7.48 (m, 1H),7.21-7.26 (m, 2H), 6.37 (m, 1H), 3.90 (m, 1H).

Example 13 Preparation of enantioenritched methyl3-cyano-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-butanoate

Enantioenritched2-(3,5-Dichlorophenyl)-4-oxo-4-pyrrol-1-yl-2-(trifluoromethyl)butanenitrile(22 mg) was taken up in methanol (2 ml) and sodium methoxide (33 mg) wasadded. The reaction was stirred at ambient temperature for 1 h beforesaturated NH₄Cl solution (4 ml) was added and the mixture extracted withEtOAc (3×8 ml). The organic portions were combined, passed through aPTFE membrane and concentrated in vacuo to give a colourless semi-solid,which was then taken up in toluene and purified by column-chromatographyon silica, eluting with cyclohexane/EtOAc to give the title compound asa colourless oil (7 mg).

¹H-NMR (400 MHz, CHLOROFORM-d): δ_(H) ppm 7.45-7.49 (m, 3H), 3.68 (s,3H), 3.36-3.39 (m, 1H).

Example 14 Preparation of enantioenritched4-(3,5-dichlorophenyl)-4-(trifluoromethyl)pyrrolidin-2-one

To a solution of methyl enantioenritched3-cyano-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-butanoate (7 mg) inmethanol (0.75 ml) was added cobalt (II) chloride hexahydrate (17 mg)followed by sodium borohydride (12 mg). The reaction mixture was stirredfor 2 h at ambient temperature before it was concentrated in vacuo andthe residue was taken up in dichloromethane (2 ml) and filtered throughCelite. The filter cake washed with further dichloromethane (3×2 ml) andthe combined filtrates were concentrated in vacuo to give a black film,which was purified by column-chromatography on silica, eluting with5-10% methanol/dichloromethane to give the title compound as acolourless oil (6 mg)

¹H-NMR (400 MHz, CDCl₃): δ_(H) ppm 7.41 (t, 1H), 7.15-7.18 (m, 2H), 5.91(br.s., 1H), 4.12 (dd, 2H), 3.81 (d, 2H).

Example 15 Preparation of methyl4-[(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methyl-benzoate

To a degassed solution of(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (100.0 mg)and methyl 4-bromo-2-methyl-benzoate (88.7 mg) in dry toluene (1.8 mL)were added sequentially sodium tert-butoxide (34.9 mg), Xantphos (12.6mg) and Pd₂(dba)₃.CHCl₃ (6.6 mg). The reaction mixture was stirred underargon at 80° C. overnight. The reaction mixture was diluted with AcOEtand washed two times with water and brine. The organic phase was dried(Na2SO4), filtered and evaporated to give 150 mg of red orange oil. Thecrude product was purified by silica gel column chromatography (Heptanein 0-100% of AcOEt) giving 51 mg (33%) of a white solid.

¹H-NMR (400 MHz, CDCl3): δ 7.93 (d, 1H, J=8.5 Hz); 7.40 (t, 1H, J=2 Hz);7.30 (s, 2H); 6.45-6.38 (m, 2H), 4.13 (d, 1H, J=10.6 Hz); 3.85 (s, 3H);3.82 (d, 1H, J=10.6 Hz); 3.66-3.48 (m, 2H); 2.92-2.82 (m, 1H); 2.63 (s,3H); 2.60-2.49 (m, 1H) ppm.

¹⁹F-NMR (400 MHz, CDCl3): 6-73.11 ppm.

¹³C-NMR (400 MHz, CDCl3): δ 167.74; 148.89; 142.98; 140.46; 135.30;133.02; 128.87; 126.83; 117.39; 114.25; 108.78; 54.47; 53.17; 51.21;46.40; 31.72; 22.71 ppm.

Example 16 Preparation of4-[(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methyl-benzoicacid

Methyl4-[(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methyl-benzoate(31.0 mg) was dissolved in tetrahydrofuran (0.36 mL). Potassiumhydroxide (300 mg) in MeOH/H2O (0.36 ml/0.36 ml) was added at RT. Thereaction was stirred at 40° C. for 72 h. The aqueous layer was extractedwith ether, then it was acidified until pH=1 with aq. HCl and extractedwith dichloromethane. The organic phase was dried (Na₂SO₄), filtered andevaporated in vacuum to give 26 mg (85%) of the desired product as awhite solid.

¹H-NMR (400 MHz, CDCl3): δ 8.01 (d, 1H, J=8 Hz); 7.40 (t, 1H, J=2 Hz);7.30 (s, 2H); 6.48-6.40 (m, 2H), 4.13 (d, 1H, J=11 Hz); 3.82 (d, 1H,J=11 Hz); 3.66-3.48 (m, 2H); 2.92-2.82 (m, 1H); 2.65 (s, 3H); 2.62-2.48(m, 1H) ppm.

Example 17 Preparation of4-[(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-N-(1,1-dioxothietan-3-yl)-2-methyl-benzamide

To a suspension of4-[(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methyl-benzoicacid (20.0 mg) in dry dichloromethane (1 mL) were added sequentially3-hydroxytriazolo[4,5-b]pyridine (7.2 mg, 1.100),3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride(10.1 mg) and a solution of 1,1-dioxothietan-3-amine hydrochloride (9.1mg) and triethylamine (14.5 mg) in dichloromethane. The yellow solutionstirred under argon for 20 h at RT. The reaction mixture was dilutedwith DCM, washed with a saturated solution of NH₄Cl and brine. Theorganic phase was dried (Na₂SO₄), filtered and evaporated in vacuum togive 16 mg (65%) of white solid.

¹H-NMR (400 MHz, CDCl₃): δ 7.42-7.38 (m, 2H); 7.31-7.29 (m, 2H);6.44-6.39 (m, 2H); 6.33 (d, 1H, 6.6 Hz); 4.91-4.83 (m, 1H); 4.66-4.57(m, 2H); 4.10 (d, 1H, J=10.6 Hz); 4.06-3.98 (m, 2H); 3.82 (d, 1H, J=10.6Hz); 3.64-3.45 (m, 2H); 2.92-2.84 (m, 1H); 2.61-2.53 (m, 1H); 2.60 (s,3H) ppm.

Chiral HPLC analysis (Chiralpack® IA 0.46 cm×10 cm,Heptane:2-propanol:diethylamine=70:30:0.1, Flow rate: 1 ml/min;Detection: 288 nm): retention time 5.61 minutes (majorenantiomer, >99%), 8.46 minutes (minor enantiomer, not observed).

Example 18 (Reference) Preparation of(3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine and(3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine

Preparative Method:Column: 250×30 mm CHIRALPAK® ID 5 μmMobil phase: Carbon dioxide (Methanol+1% Diethylamine) 95/5Flow rate: 120 mL/minDetection: UV 220 nmOutlet Pressure: 130 barTemperature: 25° C.Analytical Method:Column: 250×4.6 mm CHIRALPAK® IA 5 μmMobil phase: Heptane:2-propanol: diethylamine=70:30:0.1Flow rate: 1 mL/minDetection: UV 270 nmTemperature: 25° C.Retention time 5.15 minutes (S-enantiomer), 6.96 minutes (R-enantiomer)391 mg of (3S)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine(first eluting enantiomer, >99% enantiomeric excess) and 400 mg of(3R)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (secondeluting enantiomer, >98% enantiomeric excess were prepared from 958 mgof racemic 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine.(Enantiomeric excess is defined as the absolute difference between themole fraction of each enantiomer.)

The invention claimed is:
 1. A compound, wherein the compound is acompound of formula IIc,

wherein P is alkyl, hydroxy, alkoxy, aryloxy, alkylsulfinyl, orarylsulfinyl, each optionally substituted, R¹ is chlorodifluoromethyl ortrifluoromethyl, and R² is aryl or heteroaryl, each optionallysubstituted; a compound of formula III,

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, and R² is aryl orheteroaryl, each optionally substituted; a compound of formula IV,

wherein P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, arylor heteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom, R¹ is chlorodifluoromethyl ortrifluoromethyl, and R² is aryl or heteroaryl, each optionallysubstituted; a compound of formula V,

wherein P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, arylor heteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom, R¹ is chlorodifluoromethyl ortrifluoromethyl, and R² is aryl or heteroaryl, each optionallysubstituted; a compound of formula VI,

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, and R² is aryl orheteroaryl, each optionally substituted; a compound of formula VII,

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, and R² is aryl orheteroaryl, each optionally substituted; a compound of formula VIII,

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, and R² is aryl orheteroaryl, each optionally substituted; a compound of formula X,

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, and R² is aryl orheteroaryl, each optionally substituted; a compound of formula XIV,

wherein P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, arylor heteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom, R¹ is chlorodifluoromethyl ortrifluoromethyl, R² is aryl or heteroaryl, each optionally substituted,and A′ is optionally substituted aryl or optionally substitutedheteroaryl; a compound of formula XV,

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, R² is aryl orheteroaryl, each optionally substituted, and A′ is optionallysubstituted aryl or optionally substituted heteroaryl; a compound offormula XVIII,

wherein P is alkyl, aryl or heteroaryl, each optionally substituted,wherein the heteroaryl is connected at P via a ring carbon atom, R¹ ischlorodifluoromethyl or trifluoromethyl, and R² is aryl or heteroaryl,each optionally substituted; or a compound of formula XII,

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, R² is aryl orheteroaryl, each optionally substituted, and A′ is optionallysubstituted aryl or optionally substituted heteroaryl.
 2. A compound ofclaim 1, wherein the compound is of formula XII,

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, R² is aryl orheteroaryl, each optionally substituted, and A′ is optionallysubstituted aryl or optionally substituted heteroaryl.
 3. A mixturecomprising a compound of IIc and a compound of formula IIcA,

wherein P is alkyl, hydroxy, alkoxy, aryloxy, alkylsulfinyl, orarylsulfinyl, each optionally substituted, R¹ is chlorodifluoromethyl ortrifluoromethyl, R² is aryl or heteroaryl, each optionally substituted,and wherein the mixture is enriched for the compound of formula IIc; amixture comprising a compound of formula III and a compound of formulaIIIA,

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, R² is aryl orheteroaryl, each optionally substituted, and wherein the mixture isenriched for the compound of formula III; a mixture comprising acompound of formula IV and a compound of formula IVA,

P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, aryl orheteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom, R¹ is chlorodifluoromethyl ortrifluoromethyl, R² is aryl or heteroaryl, each optionally substituted,and wherein the mixture is enriched for the compound of formula IV; amixture comprising a compound of formula V and a compound of formula VA,

wherein P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, arylor heteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom, R¹ is chlorodifluoromethyl ortrifluoromethyl, R² is aryl or heteroaryl, each optionally substituted,and wherein the mixture is enriched for the compound of formula V; amixture comprising a compound of formula VI and a compound of formulaVIA

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, R² is aryl orheteroaryl, each optionally substituted, and wherein the mixture isenriched for the compound of formula VI; a mixture comprising a compoundof formula VII and a compound of formula VIIA

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, R² is aryl orheteroaryl, each optionally substituted, and wherein the mixture isenriched for the compound of formula VII; a mixture comprising acompound of formula VIII and a compound of formula VIIIA

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, R² is aryl orheteroaryl, each optionally substituted, and wherein the mixture isenriched for the compound of formula VIII; a mixture comprising acompound of formula X and a compound of formula XA

R¹ is chlorodifluoromethyl or trifluoromethyl, R² is aryl or heteroaryl,each optionally substituted, and wherein the mixture is enriched for thecompound of formula X; a mixture comprising a compound of formula XIIand a compound of formula XIIA

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, R² is aryl orheteroaryl, each optionally substituted, A′ is optionally substitutedaryl or optionally substituted heteroaryl, and wherein the mixture isenriched for the compound of formula XII; a mixture comprising acompound of formula XIV and a compound of formula XIVA

wherein P is hydroxy, alkoxy, aryloxy, alkylsulfinyl, arylsulfinyl, arylor heteroaryl, each optionally substituted, and wherein the heteroarylcontains at least one ring nitrogen atom, and the heteroaryl isconnected at P via a ring nitrogen atom, R¹ is chlorodifluoromethyl ortrifluoromethyl, R² is aryl or heteroaryl, each optionally substituted,A′ is optionally substituted aryl or optionally substituted heteroaryl,and wherein the mixture is enriched for the compound of formula XIV; amixture comprising a compound of formula XV and a compound of formulaXVA

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, R² is aryl orheteroaryl, each optionally substituted, A′ is optionally substitutedaryl or optionally substituted heteroaryl, and wherein the mixture isenriched for the compound of formula XV; a mixture comprising a compoundof formula XVIII and a compound of formula XVIIIA

wherein P is alkyl, aryl or heteroaryl, each optionally substituted,wherein the heteroaryl is connected at P via a ring carbon atom, R¹ ischlorodifluoromethyl or trifluoromethyl, R² is aryl or heteroaryl, eachoptionally substituted, and wherein the mixture is enriched for thecompound of formula XVIII; or a compound of formula XXIX, XXX, XXXI,XXXII, or XXXIII

wherein R¹ is chlorodifluoromethyl or trifluoromethyl, and R² is aryl orheteroaryl, each optionally substituted.